Immune Modulatory Compositions

ABSTRACT

A class of phosphorus containing polycyclic compounds of general formula I, of general formula I′ or of general formula I″, wherein B 1 , B 2 , R 1 , R 2 , R 1′ , X 1 , X 2 , Y 1 , Y 2 , B L1 , B L2 , Z 1 , and Z 2  are defined herein, that may be useful as modulators of type I interferon production, specifically as STING modulating agents, are provided. Also, provided are use of such compounds.

PRIORITY INFORMATION

This application claims priority to U.S. Provisional Application No.62/545,865 filed Aug. 15, 2017. The content of the above application isincorporated by reference in its entirety.

FIELD OF THE INVENTION

This invention relates to cyclic dinucleotides (CDNs) and cyclicdinucleotide analogues as anticancer therapeutics, cancer vaccineadjuvants and as anti-infectious agents. Specifically, the inventionconcerns novel chemical compositions useful as therapeutics, vaccineadjuvants and/or immune modulators for prophylactic and/or therapeuticuse in the treatment of autoimmune diseases, infectious diseases,inflammatory diseases including cancers and allergies in human or animalpopulations, and useful as active ingredients in pharmaceuticalcompositions.

BACKGROUND OF THE INVENTION

Viral and bacterial infections are major causes of morbidity andmortality in humans, accounting for a third of the deaths that occurglobally each year. Certain infectious agents also cause cancer and arethought to be associated with other chronic diseases such asencephalitis and meningitis. The direct healthcare cost and indirectproductivity cost associated with these diseases are very high, andaffect the population disproportionately. Often, viral and bacterialinfections can reach epidemic proportions in poor countries and canresult in large number of deaths. Both prophylactic and therapeuticinterventions are important in preventing or controlling the onslaughtof infectious agents. In this respect, agents that might act as immuneboosters, preferably through aiding both humoral and innate immunity,are of high importance as immune adjuvants and prophylactics.

Research suggests that cancer is an inflammatory disease often driven bythe lack of sufficient immune response to check the growth andpropagations of malignant cells. Thus, the lack of an adequate immuneresponse can play a central role in all aspects of cancer growth andmetastases. The relevance of the role of the immune system has beenclinically validated by the clinical success and the recent approval ofcheckpoint inhibitors and other immuno-oncology drugs. Novel immunemodulators may be effective in treating various types of cancer, and mayovercome deficiencies the current checkpoint inhibitors have. Recently,cyclic dinucleotides have emerged as powerful immune modulators throughtheir binding and activation of an endoplasmic reticulum bound proteincalled STING, an acronym for STimulator of INterferon Genes.

Cyclic guanosine adenosine monophosphate synthase (cGAS) is theprincipal pattern recognition receptor that senses pathogenic versusself DNA in the cytosol and catalyzes the production of cyclic GuanosineAdenosine MonoPhosphate (cGAMP), one of the endogenous cyclicdinucleotides (Sun, L. et al. Science 2013, 339, 786-791) that serves asa second messenger to activate innate immune responses (Jiaxi Wu et al.Science 2013, 339, 826-830). The mechanism by which cGAMP activates theimmune response is through its binding to the endoplasmic reticulumbound protein STING (G. N. Barber, Immunol. Rev. 2011, 243, 99) and itsactivation. STING activation triggers a downstream signaling cascadethat results in activation of cytosolic kinases IKK (I-kappa-B Kinase)and TBK1 (TANK Binding Kinase 1), which activates the transcriptionfactors NF-kB (Nuclear Factor kappa light chain enhancer of activated Bcells) and IRF3 (Interferon Regulatory Factor 3), respectively.Translocation of NF-kB and IRF3 to the nucleus leads to the induction oftype I interferons. Type I interferon induction has functionalconsequences for the treatment of cancer, viral diseases and bacterialinfections. Following examples of STING modulators, specifically STINGagonists, described in the art mainly concern 1) cancer immunotherapyand 2) anti-viral therapy. However, STING modulators may be useful intreating many types of autoimmune diseases, inflammatory conditions andbacterial infections, as will be described in the present disclosure.

Cancer Immunotherapy:

Many recent high impact publications have underscored the effectivenessof STING activation as a non-specific cancer immunotherapy paradigm, andits translational capability has been highlighted. For example, Fu etal. found that co-administration of cyclic dinucleotides with a cellularcancer vaccine called STINGVAX was effective against multiple types oftumors in mouse models. Furthermore, they showed that stronger STINGbinding through chemical modification of CDNs increased antitumoractivity (Science Translational Medicine, 2015, 7, pp. 283ra52). Anotherreport by Corrales et al. demonstrated that intra-tumoral injection ofCDNs activated STING-interferon-cytotoxic T-cell pathway and inducedprofound regression of established tumors in mice, and generatedsubstantial systemic immune responses capable of rejecting distantmetastases and providing long-lived immunologic memory (Cell Reports,2015, 11, 1-13). According to these authors, “synthetic CDNs have hightranslational potential as a cancer therapeutic.” The emerging field ofCDN based cancer immunotherapy has great potential not only as cancervaccine adjuvants, but also as powerful cancer drugs in combination withcheckpoint inhibitors. However, checkpoint inhibitors are notuniversally effective; they are not very effective in tumors where theimmune system fail to recognize cancer cells as dangerous. But,combining checkpoint inhibitors and STING agonists have proven to beeffective in killing even distant metastases (Science TranslationalMedicine, 2015, 7, pp. 283ra52). The present disclosure addresses theseprevious problems in the art and is in part directed towards CDNs actingas powerful anticancer immune stimulants, either alone or incombinations with other immuno-oncology therapeutics and/orchemotherapeutics, and/or DNA hypomethylating agents.

Anti-Viral Therapy Using STING Agonists—Treating HBV Infection as anExample:

Chronic hepatitis B virus (HBV) infection is notoriously difficult totreat, let alone cure, in spite of a number of nucleoside analogues(Nucs) available in the market. Long term treatment with Nucs andinterferon is known to have therapeutic effect. However, HBV surfaceantigen (HBsAg) seroconversion, the sign of a successful immunologiccontrol of HBV, or a “functional cure,” is rarely achieved with thecurrent therapies. With over 400 million people chronically infectedwith HBV worldwide, the number of cases of liver fibrosis, cirrhosis andhepatocellular carcinoma resulting from long term infection is rising atan alarming rate. Thus, there is a need for effective anti HBV therapythat is robust and sustainable enough to clear the host incorporatedviral genome. Recent reports suggest (Guo F, et al. Antimicrob AgentsChemother. 2015, 59, 1273-81) that the restoration of host innate andHBV-specific adaptive immune responses may be essential for a functionalcure of chronic HBV infection (Chang J, et al. Antiviral Res96:405-413).

Chronic HBV infection results from failed immune response to the onsetof HBV infection. Typically, pathogen associated molecular patterns(PAMP) are sensed by host mediated pattern recognition receptors (PRRS)and puts up a strong immune response. But HBV has been shown to inducenegligible innate immune responses during the early phase of infection.In fact, Type I interferon (IFN), a hallmark of antiviral innatesignaling, is either undetectable or missing in most cases of HBVpatients, and there is no concrete evidence that IFNs are produced inHBV patients (Dunn C, et al. Gastroenterology 2009, 137, 1289-1300).Yet, evidence suggests that HBV is sensitive to ligand mediatedactivation of STING-IFN pathway, and resulting antiviral response isstrong and sustainable (Guo F, et al. Antimicrob Agents Chemother. 2015,59, 1273-81). Another report has revealed that STING is a new target ofthe viral polymerase to antagonize the IFN induction against HBV (Liu Y,et al. J. Virol. 2015, 89, 2287-2300). When this is coupled with thefact that STING agonists induce an innate antiviral immune responseagainst HBV, it may be possible that a viral polymerase inhibitor suchas ribavirin or entecavir or any other Nucs and a CDN might have thedouble effect of stopping replication and providing immune boost throughSTING activation. From a clinical perspective, it is possible to‘sandwich’ a STING agonist treatment with Nuc therapy that clears mostof the virus, followed by STING therapy effectively clearing HBV cccDNA(covalently closed circular DNA) (interferon is produced in thenucleus), which will again be followed by nuc therapy to clear anymature virus that may have entered the cytosol. In another aspect, a CDNSTING agonist can be specifically and selectively delivered to livercells, thus restricting the systemic effect of the drug. This approachcan achieve two objectives: 1) decreased toxicity to other healthyorgans due to decreased dose and 2) improved efficacy due to selectivedelivery to hepatocytes, the host cells of HBV.

The present disclosure is intended to provide novel STINGagonists/modulators as prophylactics and/or therapeutics in thetreatment of cancers, viral diseases and bacterial infections.

SUMMARY OF THE INVENTION

Embodiments of the present invention include STING agonists and STINGantagonists or STING binding ligands or STING modulators in general, andare further illustrated by the classes, subclasses, and speciesdisclosed herein.

The compounds disclosed herein have several advantages over naturallyoccurring cyclic dinucleotides (CDNs) or other modified CDNs becausethey may be able to activate one or more known human STING alleles.Further embodiments are provided for treating diseases in a subject,comprising administering to the subject an effective amount of acompound as described herein. Such compounds may be used as STINGagonists or antagonists. In further embodiments, there are providedcompositions and methods concerning methods for treating cancer in asubject comprising administering to the subject an effective amount of astimulator of interferon genes (STING) agonist, wherein the STINGagonist is administered intratumorally.

All patents and publications mentioned in the specification areindicative of the levels of skill of those skilled in the art to whichthe invention pertains. All references cited in this disclosure areincorporated by reference to the same extent as if each reference hadbeen incorporated by reference in its entirety individually.

One skilled in the art would readily appreciate that the presentinvention is well adapted to carry out the objects and obtain the endsand advantages mentioned, as well as those inherent therein. The methodsand compositions described herein as presently representative ofpreferred embodiments are exemplary and are not intended as limitationson the scope of the invention. Changes therein and other uses will occurto those skilled in the art, which are encompassed within the spirit ofthe invention and are defined by the scope of the claims.

The abbreviations used herein have their conventional meaning as knownto the practitioner of chemistry and biology and within the chemical andbiological arts. The chemical structures and formulae set forth hereinare constructed according to the conventional rules of chemical valencyknown in the chemical arts.

The chemical structures disclosed herein are also meant to include allisomeric (e.g., enantiomeric, diastereomeric, and geometric (orconformational)) forms of the structure; for example, the R and Sconfigurations for each asymmetric center, Z and E double bond isomers,and Z and E conformational isomers. Therefore, single stereochemicalisomers as well as enantiomeric, diastereomeric, and geometric (orconformational) mixtures of the present compounds are within the scopeof the invention. Unless otherwise stated, all possible tautomers of thecompounds of the invention are within the scope of the invention.Additionally, unless otherwise stated, structures depicted hereininclude compounds that one may obtain by enriching one or more atoms.For example, any compounds with the replacement of one or more hydrogenatoms by deuterium or tritium, or the replacement of a carbon atom by a¹³C- or ¹⁴C-enriched carbon are within the scope of this invention. Suchcompounds may be used as, for example, analytical tools, probes inbiological assays, or therapeutic agents in accordance with the presentinvention.

The following definitions shall apply unless otherwise indicated. Forpurposes of this disclosure, the chemical elements are identified inaccordance with the Periodic Table of the Elements, IUPAC version, dated1 May 2013. Additionally, general principles of organic chemistry aredescribed in “Organic Chemistry”, T. W. Graham Solomons, Craig B.Fryhle, Scott A. Snyder, Wiley; 11^(th) edition (Jan. 17, 2013) and“March's Advanced Organic Chemistry”, 5th Ed., Ed.: Smith, M. B. andMarch, J., John Wiley & Sons, New York: 2001, the entire contents ofwhich are hereby incorporated by reference.

The terms “Treatment” or “treating” includes (1) Curing a disease in asubject or patient experiencing or displaying the pathology orsymptomatology of the disease (e.g. eliminating the diseases) (2)inhibiting further progression in a subject or patient of the pathologyand/or symptomatology, (3) ameliorating a disease in a subject orpatient that is experiencing or displaying the pathology orsymptomatology of the disease (e.g., reversing the pathology and/orsymptomatology), (4) effecting any measurable decrease in a disease in asubject or patient that is experiencing or displaying the pathology orsymptomatology of the disease and/or (5) eliminating or suppressing thepresence of a pathogen that is causative of a disease (e.g. eliminatinghepatitis B virus in a subject infected with hepatitis B virus andshowing pathology and symptoms of hepatitis B virus infection). In someembodiments, treating cancer is further defined as reducing the size ofa tumor or inhibiting growth of a tumor or eliminating the presence of atumor. In particular embodiments, the subject is a human.

In some embodiments the treatment may comprise of administering thecompositions or compounds described herein to a subject in need thereofby a variety of routes in formulations containing pharmaceuticallyacceptable carriers, adjuvants and vehicles. Such administration routesmay be systemic or local and may include, but not limited to,parenteral, intratumoral, subcutaneous, intravenous, intramuscular,intraarterial, intradermal, intrathecal, intranasal, intraperitoneal,intra-cerebroventricular, and epidural administrations.

In another embodiment, use of STING agonists along with chemotherapy areprovided. For example, anthracyclins can improve efficacy ofimmunotherapy by increasing the sensitivity of tumor cells to CD8positive T cells, also called immune effector cells or cytotoxic T cells(Zhang et al. Cancer Letters 2015, 369, 331-335). Anthracyclines arealso known to eliminate myeloid derived suppressor cells (MDSCs) whichare known immune suppressants (Alizadeh et al. Cancer Research 2014, 74,104-118). Further embodiments include the use of following chemotherapydrugs with STING modulators of the present invention: Doxorubicin,Doxil, epirubicin, daunorubicin, cyclophosphamide, ara-C, ara-A, 5-FU,capecitabin, oxaliplatin, carboplatin, paclitaxel, campothesin,irinotecan, topotecan, Abraxane, vincristine, vinblastine and celecoxib.

Another embodiment includes the use of epigenetic modulators, such asDNA methyl transferase (DNMT) inhibitors and histone deacetylase (HDAC)inhibitors, in combination with STING modulators for cancerimmunotherapy. De novo methylation of immune related genes is known tosupport T cell exhaustion which is a primary reason for immunesuppression against cancer cells. Inhibition of de novo methylation inimmune cells has shown CD8 positive T cell rejuvenation and improvedcancer cell killing (Ghoneim et al. Cell 2017, 170, 142-157). Thus,embodiments include the following drugs used in combination therapy withSTING agonists: Vidaza (5-azacytidine), decitabine, guadecitabine,zebularine, 2′-deoxyzebularine, varinostat, trichostatin A,panobinostat, sodium butyrate and romidepsin.

Unless otherwise specified, both D- and L-stereoisomers of the declaredstructures, and mixtures thereof, are within the scope of thisdisclosure. The term “acyl,” as used herein, represents a hydrogen or analkyl group that is attached to the parent molecular group through acarbonyl group, as defined herein, and is exemplified by formyl, acetyl,propionyl, butanoyl and the like. Exemplary unsubstituted acyl groupsinclude from 1 to 7, from 1 to 11, or from 1 to 21 carbons. In someembodiments, the alkyl group is further substituted with 1, 2, 3, or 4substituents as described herein.

The term “aliphatic” or “aliphatic group”, as used herein, means astraight-unbranched carbon chain or branched carbon chain, substitutedor unsubstituted carbon chain that is completely saturated or thatcontains one or more units of unsaturation, or a monocyclic hydrocarbonor bicyclic hydrocarbon that is completely saturated or that containsone or more units of unsaturation, but which is not aromatic (alsoreferred to herein as “carbocyclic,” “cycloaliphatic” or “cycloalkyl”),that has a single point of attachment to the rest of the molecule.Unless otherwise specified, aliphatic groups may contain 1-12 aliphaticcarbons atoms, 1-10aliphatic carbon atoms, 1-8 aliphatic carbon atoms or1-6 aliphatic carbon atoms. In some embodiments, aliphatic groupscontain 1-5 aliphatic carbon atoms. In some embodiments, aliphaticgroups contain 1-4 aliphatic carbon atoms. In some embodiments,aliphatic groups contain 1-3 aliphatic carbon atoms, and in yet otherembodiments, aliphatic groups contain 1-2 aliphatic carbon atoms. Insome embodiments, “cycloaliphatic” (or “carbocycle” or “cycloalkyl”)refers to a monocyclic C₃-C₆ hydrocarbon that is completely saturated orthat contains one or more units of unsaturation, but which is notaromatic, that has a single point of attachment to the rest of themolecule. Suitable aliphatic groups include, but are not limited to,linear or branched.

The term “heteroatom” means one or more of oxygen, sulfur, nitrogen,phosphorus, boron, or silicon (including, any oxidized form of nitrogen,sulfur, phosphorus, or silicon; a quaternized form of any basic nitrogenor; a substitutable nitrogen of a heterocyclic ring, for example N (asin 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR+ (as inN-substituted pyrrolidinyl)).

The term “unsaturated,” as used herein, means that a moiety has one ormore units of unsaturation.

The term “alkyl,” as used herein, refers to saturated, straight- orbranched-chain hydrocarbon radicals derived from an aliphatic moietycontaining between one and six carbon atoms by removal of a singlehydrogen atom. Unless otherwise specified, alkyl groups contain 1-12carbon atoms. In certain embodiments, alkyl groups contain 1-8 carbonatoms. In certain embodiments, alkyl groups contain 1-6 carbon atoms. Insome embodiments, alkyl groups contain 1-5 carbon atoms, in someembodiments, alkyl groups contain 1-4 carbon atoms, in some embodimentsalkyl groups contain 1-3 carbon atoms, and in some embodiments alkylgroups contain 1-2 carbon atoms. Examples of alkyl radicals include, butare not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl,iso-butyl, sec-butyl, sec-pentyl, iso-pentyl, tertiary-butyl, n-pentyl,neopentyl, n-hexyl, sec-hexyl, n-heptyl, n-octyl, n-decyl, n-undecyl,dodecyl, and the like.

The term “alkenyl,” as used herein, denotes a monovalent group derivedfrom a straight- or branched-chain aliphatic moiety having at least onecarbon-carbon double bond by the removal of set of hydrogen atoms.Unless otherwise specified, alkenyl groups contain 2-12 carbon atoms. Incertain embodiments, alkenyl groups contain 2-8 carbon atoms. In certainembodiments, alkenyl groups may contain 2-6 carbon atoms, 2-5 carbonatoms, 2-4 carbon atoms, 2-3 carbon atoms, and in some embodimentsalkenyl groups contain 2 carbon atoms. Alkenyl groups include, forexample, ethenyl, propenyl, butenyl, 1-methyl-2-buten-1-yl, and thelike.

The term “alkynyl,” as used herein, refers to a monovalent group derivedfrom a straight- or branched-chain aliphatic moiety having at least onecarbon-carbon triple bond. Unless otherwise specified, alkynyl groupscontain 2-12 carbon atoms. In certain embodiments, alkynyl groupscontain 2-8 carbon atoms. In certain embodiments, alkynyl groups contain2-6 carbon atoms. In some embodiments, alkynyl groups contain 2-5 carbonatoms, in some embodiments, alkynyl groups contain 2-4 carbon atoms, insome embodiments alkynyl groups contain 2-3 carbon atoms, and in someembodiments alkynyl groups contain 2 carbon atoms. Representativealkynyl groups include, but are not limited to, ethynyl, 2-propynyl(propargyl), 1-propynyl, and the like.

The term “alkylene” refers to a bivalent alkyl group. An “alkylenechain” is a polymethylene group, i.e., —(CH₂)_(n)—, wherein n is apositive integer, preferably from 1 to 6, from 1 to 4, from 1 to 3, from1 to 2, or from 2 to 3. A substituted alkylene chain is a polymethylenegroup in which one or more methylene hydrogen atoms are replaced with asubstituent. Suitable substituents include those described below for asubstituted aliphatic group.

The term “alkenylene” refers to a bivalent alkenyl group. A substitutedalkenylene chain is a polymethylene group containing at least one doublebond in which one or more hydrogen atoms are replaced with asubstituent. Suitable substituents include those described below.

The term “halo,” as used herein, represents a halogen selected frombromine, chlorine, iodine, or fluorine. The term “halogen” means F, Cl,Br, or I.

The term “haloalkoxy,” as used herein, represents an alkoxy group, asdefined herein, substituted by a halogen group (i.e., F, Cl, Br, or I).A haloalkoxy may be substituted with one, two, three halogens. In thecase of alkyl groups of two carbons or more, haloalkoxy may besubstituted with one, two, three, four, five or six halogens.

Haloalkoxy groups include perfluoroalkoxys (e.g., —OCF₃, —OCHF₂, —OCH₂F,—OCCl₃, —OCH₂CH₂Br, —OCH₂CH(CH₂CH₂Br)CH₃, —OCHICH₃, and —OCF₂CF₃). Insome embodiments, the haloalkoxy group can be further substituted with1, 2, 3, or 4 substituent groups as described herein for alkyl groups.The term “haloalkyl,” as used herein, represents an alkyl group, asdefined herein, substituted by a halogen group (i.e., F, Cl, Br, or I).A haloalkyl may be substituted with one, two, three, or, in the case ofalkyl groups of two carbons or more, four halogens. Haloalkyl groupsinclude perfluoroalkyls (e.g., —CF₃), —CHF₂, —CH₂F, —CH₂CH₂Br,—CH₂CH(CH₂CH₂Br)CH₃, —CHICH₃ and —CF₂CF₂. In some embodiments, thehaloalkyl group can be further substituted with 1, 2, 3, or 4substituent groups as described herein for alkyl groups.

The term “aryl” used alone or as part of a larger moiety as in“aralkyl,” “aralkoxy,” or “aryloxyalkyl,” refers to monocyclic andbicyclic ring systems having a total of five to ten ring members,wherein at least one ring in the system is aromatic and wherein eachring in the system contains three to seven ring members. The term “aryl”may be used interchangeably with the term “aryl ring”. In someembodiments, an 8-10 membered bicyclic aryl group is an optionallysubstituted naphthyl ring. In certain embodiments of the presentinvention, “aryl” refers to an aromatic ring system which includes, butnot limited to, phenyl, biphenyl, naphthyl, anthracyl and the like,which may bear one or more substituents. Also included within the scopeof the term “aryl,” as it is used herein, is a group in which anaromatic ring is fused to one or more non-aromatic rings, such asindanyl, phthalimidyl, naphthimidyl, phenanthridinyl, ortetrahydronaphthyl, and the like.

The terms “heteroaryl” and “heteroar-,” used alone or as part of alarger moiety, e.g., “heteroaralkyl,” or “heteroaralkoxy,” refer togroups having 5 to 10 ring atoms, preferably 5, 6, or 9 ring atoms;having 6, 10, or 14 n electrons shared in a cyclic array; and having, inaddition to carbon atoms, from one to five heteroatoms. Heteroarylgroups include, without limitation, thienyl, furanyl, pyrrolyl,imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl,oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl,pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl,naphthyridinyl, and pteridinyl.

The terms “heteroaryl” and “heteroar-”, as used herein, also includegroups in which a heteroaromatic ring is fused to one or more aryl,cycloaliphatic, or heterocyclyl rings, where the radical or point ofattachment is on the heteroaromatic ring. Nonlimiting examples includeindolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl,indazolyl, benzimidazolyl, benzthiazolyl, quinolyl, isoquinolyl,cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolizinyl,carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl,tetrahydroquinolinyl, tetrahydroisoquinolinyl, andpyrido[2,3-b]-1,4-oxazin-3(4H)-one.

A heteroaryl group may be mono- or bicyclic. The term “heteroaryl” maybe used interchangeably with the terms “heteroaryl ring,” “heteroarylgroup,” or “heteroaromatic,” any of which terms include rings that areoptionally substituted. The term “heteroaralkyl” refers to an alkylgroup substituted by a heteroaryl, wherein the alkyl and heteroarylportions independently are optionally substituted.

As used herein, the terms “heterocycle,” “heterocyclyl,” “heterocyclicradical,” and “heterocyclic ring” are used interchangeably and refer toa 5-, 6- or 7-membered ring, unless otherwise specified, containing one,two, three, or four heteroatoms independently selected from the groupconsisting of nitrogen, oxygen, and sulfur. The 5-membered ring has zeroto two double bonds, and the 6- and 7-membered rings have zero to threedouble bonds. Exemplary unsubstituted heterocyclyl groups are of 1 to 12(e.g., 1 to 11, 1 to 10, 1 to 9, 2 to 12, 2 to 11, 2 to 10, or 2 to 9)carbons. The term “heterocyclyl” also represents a heterocyclic compoundhaving a bridged multi-cyclic structure in which one or more carbonsand/or heteroatoms bridges two non-adjacent members of a monocyclicring, e.g., a quinuclidinyl group. The term “heterocyclyl” includesbicyclic, tricyclic, and tetracyclic groups in which any of the aboveheterocyclic rings is fused to one, two, or three carbocyclic rings,e.g., an aryl ring, a cyclohexane ring, a cyclohexene ring, acyclopentane ring, a cyclopentene ring, or another monocyclicheterocyclic ring, such as indolyl, quinolyl, isoquinolyl,tetrahydroquinolyl, benzofuryl, benzothienyl and the like. Examples offused heterocyclyls include tropanes and1,2,3,5,8,8a-hexahydroindolizine. Heterocyclics include isoxazolyl,isoxazolidiniyl, morpholinyl, thiomorpholinyl, thiazolyl, thiazolidinyl,isothiazolyl, isothiazolidinyl, indolyl, indazolyl, quinolyl,isoquinolyl, quinoxalinyl, dihydroquinoxalinyl, quinazolinyl,cinnolinyl, phthalazinyl, benzimidazolyl, benzothiazolyl, benzoxazolyl,pyrrolyl, pyrrolinyl, pyrrolidinyl, pyrazolyl, pyrazolinyl,pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl,piperidinyl, homopiperidinyl, pyrazinyl, piperazinyl, pyrimidinyl,pyridazinyl, oxazolyl, oxazolidinyl, benzothiadiazolyl, furyl, thienyl,thiazolidinyl, isothiazolyl, triazolyl, tetrazolyl, oxadiazolyl (e.g.,1,2,3-oxadiazolyl), purinyl, thiadiazolyl (e.g., 1,2,3-thiadiazolyl),tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl,dihydroindolyl, dihydroquinolyl, tetrahydroquinolyl,tetrahydroisoquinolyl, dihydroisoquinolyl, pyranyl, dihydropyranyl,dithiazolyl, benzofuranyl, isobenzofuranyl, benzothienyl, and the like,including dihydro and tetrahydro forms thereof, where one or more doublebonds are reduced and replaced with hydrogens. Still other exemplaryheterocyclyls include: 2,3,4,5-tetrahydro-2-oxo-oxazolyl;2,3-dihydro-2-oxo-1H-imidazolyl; 2,3,4,5-tetrahydro-5-oxo-1H-pyrazolyl(e.g., 2,3,4,5-tetrahydro-2-phenyl-5-oxo-1H-pyrazolyl);2,3,4,5-tetrahydro-2,4-dioxo-1H-imidazolyl (e.g.,2,3,4,5-tetrahydro-2,4-dioxo-5-methyl-5-phenyl-1H-imidazolyl);2,3-dihydro-2-thioxo-1,3,4-oxadiazolyl (e.g.,2,3-dihydro-2-thioxo-5-phenyl-1,3,4-oxadiazolyl);4,5-dihydro-5-oxo-1H-triazolyl (e.g., 4,5-dihydro-3-methyl-4-amino5-oxo-1H-triazolyl); 1,2,3,4-tetrahydro-2,4-dioxopyridinyl (e.g.,1,2,3,4-tetrahydro-2,4-dioxo-3,3-diethylpyridinyl);2,6-dioxo-piperidinyl (e.g., 2,6-dioxo-3-ethyl-3-phenylpiperidinyl);1,6-dihydro-6-oxopyridiminyl; 1,6-dihydro-4-oxopyrimidinyl (e.g.,2-(methylthio)-1,6-dihydro-4-oxo-5-methylpyrimidin-1-yl);1,2,3,4-tetrahydro-2,4-dioxopyrimidinyl (e.g.,1,2,3,4-tetrahydro-2,4-dioxo-3-ethylpyrimidinyl);1,6-dihydro-6-oxo-pyridazinyl (e.g.,1,6-dihydro-6-oxo-3-ethylpyridazinyl); 1,6-dihydro-6-oxo-1,2,4-triazinyl(e.g., 1,6-dihydro-5-isopropyl-6-oxo-1,2,4-triazinyl);2,3-dihydro-2-oxo-1H-indolyl (e.g.,3,3-dimethyl-2,3-dihydro-2-oxo-1H-indolyl and2,3-dihydro-2-oxo-3,3′-spiropropane-1H-indol-1-yl);1,3-dihydro-1-oxo-2H-iso-indolyl; 1,3-dihydro-1,3-dioxo-2H-iso-indolyl;1H-benzopyrazolyl (e.g., 1-(ethoxycarbonyl)-1H-benzopyrazolyl);2,3-dihydro-2-oxo-1H-benzimidazolyl (e.g.,3-ethyl-2,3-dihydro-2-oxo-1H-benzimidazolyl);2,3-dihydro-2-oxo-benzoxazolyl (e.g.,5-chloro-2,3-dihydro-2-oxo-benzoxazolyl);2,3-dihydro-2-oxo-benzoxazolyl; 2-oxo-2H-benzopyranyl;1,4-benzodioxanyl; 1,3-benzodioxanyl; 2,3-dihydro-3-oxo,4H-1,3-benzothiazinyl; 3,4-dihydro-4-oxo-3H-quinazolinyl (e.g.,2-methyl-3,4-dihydro-4-oxo-3H-quinazolinyl);1,2,3,4-tetrahydro-2,4-dioxo-3H-quinazolyl (e.g.,1-ethyl-1,2,3,4-tetrahydro-2,4-dioxo-3H-quinazolyl);1,2,3,6-tetrahydro-2,6-dioxo-7H-purinyl (e.g.,1,2,3,6-tetrahydro-1,3-dimethyl-2,6-dioxo-7H-purinyl);1,2,3,6-tetrahydro-2,6-dioxo-1H-purinyl (e.g., 1,2,3,6-tetrahydro-3,7-dimethyl-2,6-dioxo-1H-purinyl); 2-oxobenz[c,d]indolyl;1,1-dioxo-2H-naphth[1,8-c,d]isothiazolyl; and1,8-naphthylenedicarboxamido. Additional heterocyclics include3,3a,4,5,6,6a-hexahydro-pyrrolo[3,4-b]pyrrol-(2H)-yl, and2,5-diazabicyclo[2.2.1]heptan-2-yl, homopiperazinyl (or diazepanyl),tetrahydropyranyl, dithiazolyl, benzofuranyl, benzothienyl, oxepanyl,thiepanyl, azocanyl, oxecanyl, and thiocanyl.

As used herein, the term “partially unsaturated” refers to a ring moietythat includes at least one double or triple bond. The term “partiallyunsaturated” is intended to encompass rings having multiple sites ofunsaturation, but is not intended to include aryl or heteroarylmoieties, as herein defined.

As described herein, compounds of the invention may, when specified,contain “optionally substituted” moieties. In general, the term“substituted,” whether preceded by the term “optionally” or not, meansthat one or more hydrogens of the designated moiety are replaced with asuitable substituent. Unless otherwise indicated, an “optionallysubstituted” group may have a suitable substituent at each substitutableposition of the group, and when more than one position in any givenstructure may be substituted with more than one substituent selectedfrom a specified group, the substituent may be either the same ordifferent at every position. Combinations of substituents envisioned bythis invention are preferably those that result in the formation ofstable or chemically feasible compounds. The term “stable,” as usedherein, refers to compounds that are not substantially altered whensubjected to conditions to allow for their production, detection, and,in certain embodiments, their recovery, purification, and use for one ormore of the purposes disclosed here.

The term “protecting group,” as used herein, refers to a chemicallylabile chemical moiety that is known in the art to temporarily blockchemically reactive functional groups including, but not limited to,hydroxyl, amino and thiol groups, against undesired reactions duringsynthetic procedures. Protecting groups are typically used selectivelyand/or orthogonally to prevent reactivity of selected reactive sitesduring reactions at desired alternate reactive sites and can then beremoved to leave the unprotected group as is or available for furtherreactions. Generally, groups are protected that will be inert toreactions that modify other areas of the parent molecule for conversioninto their original groups at an appropriate time. Protecting groups asknown in the art are described generally in Peter G. M. Wuts andTheodora W. Greene, Greene's Protective Groups in Organic Synthesis,4^(th) edition, John Wiley & Sons, New York (2007).

Examples of hydroxyl protecting groups include, but are not limited to,acetyl, benzoyl, t-butyl, t-butoxymethyl, 4-dinitrophenyl, benzyl,2,6-dichlorobenzyl, diphenylmethyl, p-nitrobenzyl,bis(2-acetoxyethoxy)methyl (ACE), 2-trimethyl silylethyl, diphenylsilyl,triphenylsilyl, [(triisopropylsilyl)oxy]methyl (TOM), benzoylformate,chloroacetyl, trichloroacetyl, trifluoroacetyl, pivaloyl,p-phenylbenzoyl, 9-fluorenyl methyl carbonate, mesylate, tosylate,triphenylmethyl (trityl), monomethoxytrityl, dimethoxytrityl (DMT),trimethoxytrityl, 1(2-fluorophenyl)-4-methoxypiperidin-4-yl (FPMP),9-phenylxanthine-9-yl (Pixyl) and 9-(p-methoxyphenyl)xanthine-9-yl(MOX), benzyl, 2,6-dichlorobenzyl, t-butyldimethylsilyl,t-butyldiphenylsilyl, benzoyl, mesylate, tosylate, 9-phenylxanthine-9-yl(Pixyl) and 9-(p-methoxyphenyl)xanthine-9-yl (MOX).

Examples of amino protecting groups include, but are not limited to,carbamate-protecting groups, such as 2-trimethylsilylethoxycarbonyl(Teoc), 1-methyl-1-(4-biphenylyl)ethoxycarbonyl (Bpoc), t-butoxycarbonyl(BOC), allyloxycarbonyl (Alloc), 9-fluorenylmethyloxycarbonyl (Fmoc),and benzyloxycarbonyl (Cbz); amide-protecting groups, such as formyl,acetyl, phenoxyacetyl (Pac), trihaloacetyl, benzoyl, isobutyryl, andnitrophenylacetyl; sulfonamide-protecting groups, such as2-nitrobenzenesulfonyl; imine- and cyclic imide-protecting groups, suchas phthalimido and dithiasuccinoyl; primary amine protecting groups suchas N-(1-(4,4-dimethyl-2,6-dioxocyclohexylidene)ethyl) (Dde) andtrifluoroacetyl.

The term “ligand” means a chemical moiety that acts as a substrate or abinding partner for a naturally occurring receptor on the cell surface,an enzyme in the blood stream or in the cytosol or any other cellularcompartments such as nucleus, mitochondria, Golgi apparatus, ribosomeetc., or a naturally occurring transporter protein that typicallytransports amino acids, peptides, hormones, carbohydrates, vitamins,ions like sodium, potassium etc. and nucleosides and nucleoside analogsetc. across the cell membrane. Such ligand binding can lead to changeson such receptors, enzymes and transporters temporarily such thatligands might get internalized into the cell, might undergo structuraltransformation, or might get transported across the cell membrane.

The term “conjugate” means a larger chemical moiety formed by covalentbonding of two or more smaller chemical moieties with distinctstructures and functions through a linker moiety. In the case of aligand-CDN conjugate, a cyclic dinucleotide and a ligand, e.g. a folicacid moiety, are covalently linked together through a linker moiety.

The term “linker” means a chemical moiety that connects a “ligand” and aCDN. Such linkers can be a straight carbon chain of a series ofmethylene groups, a molecule incorporating an ester, amide, carbamate,carbonate, triazole, disulfide, thioester, ether, ethylene glycol,polyethylene glycol, secondary amine, tertiary amine, aromatic orhetero-aromatic groups or a combination of these of these groups. Suchlinkers preferably have stability in the blood stream so that theligand-CDN conjugate is intact while in circulation, but gets hydrolyzedonce inside the cell or diseased tissue.

The term “CDN” means a cyclic dinucleotide.

The term “derivative” means chemical and structural form of a naturallyoccurring or synthetic ligand that has been chemically modified to beattached to a drug through a covalent bond.

The terms “modulators” may mean either an agonist or an antagonist or abinding ligand. As an agonist the modulator increases the expression orfunctions of a biological factor. As an antagonist the modulator worksagainst or works to decrease the expression or function of a biologicalfactor. A binding ligand simply binds to the biological factor throughchemical interactions such as hydrophobic, hydrophilic, hydrogenbonding, van der waals bonding. Therefore, the terms “modulators” areinterchangeable with “agonists” or “antagonists” or “binding ligand”depending on the binding affinity and mode of binding to the biologicalfactor. The biological factor in the present application is the adaptorprotein STING.

Other objects, features and advantages of the present invention willbecome apparent from the following detailed description. It should beunderstood, however, that the detailed description and the specificexamples, while indicating preferred embodiments of the invention, aregiven by way of illustration only, as various changes and modificationswithin the spirit and scope of the invention will become apparent tothose skilled in the art from this detailed description.

DETAILED DESCRIPTION

Embodiments of the present invention include STING agonists and STINGantagonists or STING binding ligands or STING modulators in general asdescribed generally above, and are further illustrated by the classes,subclasses, and species disclosed herein. Other objects, features andadvantages of the present invention will become apparent from thefollowing detailed description. It should be understood, however, thatthe detailed description and the specific examples, while indicatingpreferred embodiments of the invention, are given by way of illustrationonly, as various changes and modifications within the spirit and scopeof the invention will become apparent to those skilled in the art fromthis detailed description.

In the present patent application, a series of cyclic dinucleotide (CDN)analogs having general formulae I, I′ and I″ which are further definedbelow in detail, and their corresponding pharmaceutically acceptablesalts, compositions, prodrugs and dosage forms and ligand-CDN conjugatesthereof are claimed.

In some embodiments, the present invention provides compounds of formulaI, and their corresponding pharmaceutically acceptable salts,compositions, prodrugs, dosage forms and conjugates thereof.

wherein:

B¹ and B² are independently and optionally selected from the groupconsisting of:

Wherein, each R³, R⁴, R⁵, R⁸, R⁹, R¹⁰, R¹ and R¹² is independently andoptionally selected from a group consisting of hydrogen, halogen, —NO₂,—CN, R, —OR, —SR, —NHR, —N(R)₂, —C(O)R, —CO₂R, —C(O)C(O)R,—C(O)CH₂C(O)R, —S(O)R, —S(O)₂R, —C(O)N(R)₂, —SO₂N(R)₂, —OC(O)R,—N(R)C(O)R, —N(R)C(═NR)N(R)₂, —C(═NR)N(R)₂, —C═NOR, —N(R)SO₂N(R)₂,—N(R)SO₂R, —OC(O)N(R)₂, or an optionally substituted group selected fromC₁₋₁₂ aliphatic, phenyl, a 3-6 membered saturated or partiallyunsaturated monocyclic carbocyclic ring, a 3-6 membered saturated orpartially unsaturated heterocyclic ring having 1-2 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, and a 5-6membered heteroaryl ring having 1-3 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur.

R⁶ is independently NH₂, NHR, OH, —OR, —SR, —N(R)₂.

R⁷ is independently halogen, NH₂, NHR, OH, OR, SH, SR, —N(R)₂ when G isa C, and R⁷ is absent when G is N.

Each R is independently selected from the group consisting of hydrogenor an optionally substituted group selected from C₁₋₆ aliphatic, phenyl,a 3-7 membered saturated or partially unsaturated carbocyclic ring, a3-7 membered saturated or partially unsaturated monocyclic heterocyclicring having 1-2 heteroatoms independently selected from nitrogen,oxygen, or sulfur, and a 5-6 membered heteroaryl ring having 1-3heteroatoms independently selected from nitrogen, oxygen, or sulfur; or:two R groups on the same nitrogen are taken together with theirintervening atoms to form an optionally substituted 3-7 memberedsaturated, partially unsaturated, or heteroaryl ring having 1-4heteroatoms independently selected from nitrogen, oxygen, or sulfur.

A, E and G are independently N, C, CR^(a) where R^(a) is independently ahalogen or H.

D is independently selected from N, CH, C—CN, C—NO₂, CR, C—NH₂, C—NHR,CN(R)₂, CF, CI, C—CONH₂, C—CONHR, C—CON(R)₂, C—CSN(R)₂, C—COOR,C—C(═NH)NH₂, C—OH, C—OR, C—C₁₋₄ alkylamino, C-di(C₁₋₄ alkyl)amino,C-(1,3-oxazol-2-yl), C-(1,3-thiazol-2-yl), or C-(imidazol-2-yl); Whereinalkyl is optionally substituted with one to three groups independentlyselected from halogen, amino, hydroxyl, carboxyl, or C₁₋₃ alkoxy.

D¹ is independently selected from N, CH, C—CN, C—NO₂, CR, C—NH₂, C—NHR,CN(R)₂, CF, CI, C—CONH₂, C—CONHR, C—CON(R)₂, C—CSN(R)₂, C—COOR,C—C(═NH)NH₂, C—OH, C—OR, C—C₁₋₄ alkylamino, C-di(C₁₋₄ alkyl)amino,C-(1,3-oxazol-2-yl), C-(1,3-thiazol-2-yl), or C-(imidazol-2-yl); Whereinalkyl is optionally substituted with one to three groups independentlyselected from halogen, amino, hydroxyl, carboxyl, or C₁₋₃ alkoxy.

J is independently selected from O, S, SO₂, NH or NR.

L is independently selected from C or N; wherein when L is N, R⁴ isabsent and when L is C, R⁴ is as defined above.

W is independently O, S or NH.

R¹ and R² are independently and optionally selected from the groupconsisting of hydrogen, halogen, —NO₂, —CN, —OR, —SR, —NHR, —N(R)₂,—C(O)R, —CO₂R, —C(O)CH₂C(O)R, —S(O)R, —S(O)₂R, —C(O)N(R)₂, —SO₂N(R)₂,—OC(O)R, —N(R)C(O)R, —N(R)N(R)₂, N(R)C(═NR)N(R)₂, —C(═NR)N(R)₂, —C═NOR,—N(R)C(O)N(R)₂, —N(R)SO₂N(R)₂, —N(R)SO₂R, —OC(O)N(R)₂, and optionallysubstituted C₁₋₁₂ aliphatic or C₁₋₄ alkoxy-C₁₋₄ alkyl;

R¹ and R² cannot be the same except for hydrogen.

B_(L1) and B_(L2) are independently and optionally a bond connecting thetwo carbons attached to each of them.

Either B_(L1) or B_(L2) may be optionally absent or both B_(L1) andB_(L2) may be absent such that no C—C bond exists

Both B_(L1) and B_(L2) cannot be a bond at the same time in the samemolecule

Each R^(1′) are independently and optionally selected from a groupconsisting of hydrogen, halogen, N₃, C(O)OH, CN, C(O)NH₂, C(S)NH₂,C(O)OR or R.

X¹ and X² are independently and optionally for each occurrence an O, S,NH, NR, CH₂, CHR, C(R)₂, C═CH₂, or C═CF₂

X³ may independently and optionally be selected from, O, NH, C═O, SO₂,C═NH, NR

Y¹ and Y² is independently and optionally for each occurrence an O, S,NH, CH₂, CF₂ or CCl₂

Z¹ and Z² are independently selected from: O⁻, S⁻, OH, SH, H, CH₃, F,BH₃ ⁻.

Alternatively, Z¹ and Z² are independently selected from OL², OCH₂CH₂L²,OCH₂OC(O)L², OCH₂OC(O)NHL², OCH₂OC(O)N(L²)₂, OCH₂OC(O)OL², OCH₂OC(O)SL²,OCH₂NHC(O)L², OCH₂SC(O)L², OCH₂(CH₂)₁₋₆OC(O)L², OCH₂(CH₂)₁₋₆SC(O)L²,OCH₂(CH₂)₁₋₆NHC(O)L², OCH₂(CH₂)₁₋₆OC(O)OL², OCH₂(CH₂)₁₋₆SC(O)OL²,OCH₂(CH₂)₁₋₆NHC(O)OL², OCH₂O(CO)C(CH₃)₃, OCH₂O(CO)C(CH₃)₂CH₂OL²,OCH₂S(CO)C(CH₃)₂CH₂OL², OCH₂CH₂O(CO)C(CH₃)₃, OCH₂CH₂S(CO)C(CH₃)₃, OCH₂CH₂ O(CO)C(CH₃)₂CH₂OL², OCH₂ CH₂ S(CO)C(CH₃)₂CH₂OL²,OCH₂CH₂S—SCH₂(CH₂)₀₋₆L², OCH₂CH₂S—SCH₂(CH₂)₀₋₆OL², —O(CH₂CH₂O)₂₋₂₀L²,—O(CH₂CH₂O)₂₋₂₀ C(O)OL², O(CH₂CH₂O)₂₋₂₀ C(O)NHL², —O(CH₂CH₂O)₂₋₂₀CH₂CH₂NHC(O)L², —O(CH₂CH₂O)₂₋₂₀ C(O)N(L²)₂, —S(CH₂CH₂O)₂₋₂₀L²,—S(CH₂CH₂O)₂₋₂₀ C(O)OL², —S(CH₂CH₂O)₂₋₂₀ C(O)NHL², —S(CH₂CH₂O)₂₋₂₀C(O)N(L²)₂.

Where L² is independently and optionally selected from any of thefollowing: H, N₃, C₁₋₂₀ straight chain alkyl, a C₁₋₂₀ straight chainalkenyl, C₁₋₂₀ alkynyl, C₃₋₆ cycloalkyl, C₁₋₆ haloalkyl, a tert-butyl, asubstituted tert-butyl, a glucuronide moiety, (J. Med. Chem. 1999, 42,3623-3628), a tyrosine, a tyrosine derivative, a lipid, adehydroascorbic acid derivative, a N-acetylgalactosamine derivative, aglucose derivative, a galactose derivative, a mannose derivative, afatty acid derivative, a natural peptide comprising of 2-13 amino acids,a modified peptide comprising of 2-13 amino acids, a sigma-2 receptorbinding ligand derivative, a retinoic acid derivative, a prostatespecific membrane antigen (PSMA) binding ligand derivative, a folic acidderivative, a glycirrhetinic acid (GA) receptor binding ligandderivative, an Asialo Glycoprotein Receptor (ASGPR) binding ligandderivative or a chemical derivative that allows selective uptake by acell through a preferentially expressed receptor or transporter thatexists on the cell surface.

In some other embodiments, the present invention provides compounds offormula I′, and its corresponding pharmaceutically acceptable salts,compositions, prodrugs, dosage forms and CDN-ligand conjugates thereof.

Wherein:

B¹ and B² are independently and optionally selected from the groupconsisting of:

each R¹ and R² are independently and optionally selected from the groupconsisting of hydrogen, halogen, —NO₂, —CN, —OR, —SR, —NHR, —N(R)₂,—C(O)R, —CO₂R, —C(O)CH₂C(O)R, —S(O)R, —S(O)₂R, —C(O)N(R)₂, —SO₂N(R)₂,—OC(O)R, —N(R)C(O)R, —N(R)N(R)₂, —N(R)C(═NR)N(R)₂, C(═NR)N(R)₂, —C═NOR,—N(R)C(O)N(R)₂, —N(R)SO₂N(R)₂, —N(R)SO₂R, —OC(O)N(R)₂, and optionallysubstituted C₁₋₁₂ aliphatic or C₁₋₄ alkoxy-C₁₋₄ alkyl;

R¹ and R² cannot be the same except for hydrogen.

B_(L2) is a bond connecting the two carbons attached to it or optionallynot a bond.

Each R^(1′) are independently and optionally selected from a groupconsisting of hydrogen, halogen, N₃, C(O)OH, CN, C(O)NH₂, C(S)NH₂,C(O)OR or R.

Each R³, R⁴, R⁵, R⁸, R⁹, R¹⁰, R¹¹ and R¹² is independently andoptionally selected from a group consisting of hydrogen, halogen, —NO₂,—CN, R, —OR, —SR, —NHR, —N(R)₂, —C(O)R, —CO₂R, —C(O)C(O)R,—C(O)CH₂C(O)R, —S(O)R, —S(O)₂R, —C(O)N(R)₂, —SO₂N(R)₂, —OC(O)R,—N(R)C(O)R, —N(R)C(═NR)N(R)₂, —C(═NR)N(R)₂, —C═NOR, —N(R)SO₂N(R)₂,—N(R)SO₂R, —OC(O)N(R)₂, or an optionally substituted group selected fromC₁₋₁₂ aliphatic, phenyl, a 3-6 membered saturated or partiallyunsaturated monocyclic carbocyclic ring, a 3-6 membered saturated orpartially unsaturated heterocyclic ring having 1-2 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, and a 5-6membered heteroaryl ring having 1-3 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur.

R⁶ is independently NH₂, NHR, OH, —OR, —SR, —N(R)₂

R⁷ is independently halogen, NH₂, NHR, OH, OR, SH, SR, —N(R)₂ when G isa C, and R⁷ is absent when G is N.

Each R is independently selected from the group consisting of hydrogenor an optionally substituted group selected from C₁₋₆ aliphatic, phenyl,a 3-7 membered saturated or partially unsaturated carbocyclic ring, a3-7 membered saturated or partially unsaturated monocyclic heterocyclicring having 1-2 heteroatoms independently selected from nitrogen,oxygen, or sulfur, and a 5-6 membered heteroaryl ring having 1-3heteroatoms independently selected from nitrogen, oxygen, or sulfur; or:two R groups on the same nitrogen are taken together with theirintervening atoms to form an optionally substituted 3-7 memberedsaturated, partially unsaturated, or heteroaryl ring having 1-4heteroatoms independently selected from nitrogen, oxygen, or sulfur.

A, E and G are independently N, C, CR^(a) where R^(a) is independentlyhalogen or H.

D is independently selected from N, CH, C—CN, C—NO₂, CR, C—NH₂, C—NHR,CN(R)₂, CF, CI, C—CONH₂, C—CONHR, C—CON(R)₂, C—CSN(R)₂, C—COOR,C—C(═NH)NH₂, C—OH, C—OR, C—C₁₋₄ alkylamino, C-di(C₁₋₄ alkyl)amino,C-(1,3-oxazol-2-yl), C-(1,3-thiazol-2-yl), or C-(imidazol-2-yl); Whereinalkyl is optionally substituted with one to three groups independentlyselected from halogen, amino, hydroxyl, carboxyl, or C₁₋₃ alkoxy.

D¹ is independently selected from N, CH, C—CN, C—NO₂, CR, C—NH₂, C—NHR,CN(R)₂, CF, CI, C—CONH₂, C—CONHR, C—CON(R)₂, C—CSN(R)₂, C—COOR,C—C(═NH)NH₂, C—OH, C—OR, C—C₁₋₄ alkylamino, C-di(C₁₋₄ alkyl)amino,C-(1,3-oxazol-2-yl), C-(1,3-thiazol-2-yl), or C-(imidazol-2-yl); Whereinalkyl is optionally substituted with one to three groups independentlyselected from halogen, amino, hydroxyl, carboxyl, or C₁₋₃ alkoxy.

J is independently selected from O, S, SO₂, NH or NR.

In structure II, L is independently selected from C or N; wherein when Lis N, R⁴ is absent and when L is C, R⁴ is as defined above.

W is independently O, S or NH.

X¹ and X² are independently and optionally for each occurrence an O, S,NH, NR, CH₂, CHR, C(R)₂, C═CH₂, or C═CF₂.

X³ may independently and optionally be selected from, O, NH, C═O, SO₂,C═NH, NR

Y¹ and Y² is independently and optionally for each occurrence an O, S,NH, CH₂, CF₂ or CCl₂

Z¹ and Z² are independently selected from: O⁻, S⁻, OH, SH, H, CH₃, F,BH₃ ⁻. It can be appreciated that the negative charges are balanced bypositive counter ions to form pharmaceutically acceptable salts.

Alternatively, Z¹ and Z² are independently selected from OL², OCH₂CH₂L²,OCH₂OC(O)L², OCH₂OC(O)NHL², OCH₂OC(O)N(L²)₂, OCH₂OC(O)OL², OCH₂OC(O)SL²,OCH₂NHC(O)L², OCH₂SC(O)L², OCH₂(CH₂)₁₋₆OC(O)L², OCH₂(CH₂)₁₋₆SC(O)L²,OCH₂(CH₂)₁₋₆NHC(O)L², OCH₂(CH₂)₁₋₆OC(O)OL², OCH₂(CH₂)₁₋₆SC(O)OL²,OCH₂(CH₂)₁₋₆NHC(O)OL², OCH₂O(CO)C(CH₃)₃, OCH₂O(CO)C(CH₃)₂CH₂OL²,OCH₂S(CO)C(CH₃)₂CH₂OL², OCH₂CH₂O(CO)C(CH₃)₃, OCH₂CH₂S(CO)C(CH₃)₃, OCH₂CH₂ O(CO)C(CH₃)₂CH₂OL², OCH₂ CH₂ S(CO)C(CH₃)₂CH₂OL²,OCH₂CH₂S—SCH₂(CH₂)₀₋₆L², OCH₂CH₂S—SCH₂(CH₂)₀₋₆OL², O(CH₂CH₂O)₂₋₂₀L²,—O(CH₂CH₂O)₂₋₂₀ C(O)OL², —O(CH₂CH₂O)₂₋₂₀ C(O)NHL², —O(CH₂CH₂O)₂₋₂₀CH₂CH₂NHC(O)L², —O(CH₂CH₂O)₂₋₂₀ C(O)N(L²)₂, —S(CH₂CH₂O)₂₋₂₀L²,—S(CH₂CH₂O)₂₋₂₀C(O)OL², —S(CH₂CH₂O)₂₋₂₀ C(O)NHL², —S(CH₂CH₂O)₂₋₂₀C(O)N(L²)₂.

Where L² is independently and optionally selected from any of thefollowing: H, N₃, C₁₋₂₀ straight chain alkyl, a C₁₋₂₀ straight chainalkenyl, C₁₋₂₀ alkynyl, C₃₋₆ cycloalkyl, C₁₋₆ haloalkyl, a tert-butyl, asubstituted tert-butyl, a glucuronide moiety, (J. Med. Chem. 1999, 42,3623-3628), a tyrosine, a tyrosine derivative, a lipid, adehydroascorbic acid derivative, a N-acetylgalactosamine derivative, aglucose derivative, a galactose derivative, a mannose derivative, afatty acid derivative, a natural peptide comprising of 2-13 amino acids,a modified peptide comprising of 2-13 amino acids, a sigma-2 receptorbinding ligand derivative, a retinoic acid derivative, a prostatespecific membrane antigen (PSMA) binding ligand derivative, a folic acidderivative, a glycirrhetinic acid (GA) receptor binding ligandderivative, an Asialo Glycoprotein Receptor (ASGPR) binding ligandderivative or a chemical derivative that allows selective uptake by acell through a preferentially expressed receptor or transporter thatexists on or exposed to the cell surface.

In some other embodiments, the present invention provides compounds offormula I″, and its corresponding pharmaceutically acceptable salts,compositions, prodrugs, dosage forms and CDN-ligand conjugates thereof.

Wherein:

B¹ and B² are independently and optionally selected from the groupconsisting of:

each R¹ and R² are independently and optionally selected from the groupconsisting of hydrogen, halogen, —NO₂, —CN, —OR, —SR, —NHR, —N(R)₂,—C(O)R, —CO₂R, —C(O)CH₂C(O)R, —S(O)R, —S(O)₂R, —C(O)N(R)₂, —SO₂N(R)₂,—OC(O)R, —N(R)C(O)R, —N(R)N(R)₂, —N(R)C(═NR)N(R)₂, —C(═NR)N(R)₂, —C═NOR,—N(R)C(O)N(R)₂, —N(R)SO₂N(R)₂, —N(R)SO₂R, —OC(O)N(R)₂, and optionallysubstituted C₁₋₁₂ aliphatic or C₁₋₄ alkoxy-C₁₋₄ alkyl;

R¹ and R² cannot be the same except for hydrogen.

B_(L2) is a bond connecting the two carbons attached to it or optionallynot a bond.

Each R^(1′) are independently and optionally selected from a groupconsisting of hydrogen, halogen, N₃, C(O)OH, CN, C(O)NH₂, C(S)NH₂,C(O)OR or R.

Each R³, R⁴, R⁵, R⁸, R⁹, R¹⁰, R¹¹ and R¹² is independently andoptionally selected from a group consisting of hydrogen, halogen, —NO₂,—CN, R, —OR, —SR, —NHR, —N(R)₂, —C(O)R, —CO₂R, —C(O)C(O)R,—C(O)CH₂C(O)R, —S(O)R, —S(O)₂R, —C(O)N(R)₂, —SO₂N(R)₂, —OC(O)R,—N(R)C(O)R, —N(R)C(═NR)N(R)₂, —C(═NR)N(R)₂, —C═NOR, —N(R)SO₂N(R)₂,—N(R)SO₂R, —OC(O)N(R)₂, or an optionally substituted group selected fromC₁₋₁₂ aliphatic, phenyl, a 3-6 membered saturated or partiallyunsaturated monocyclic carbocyclic ring, a 3-6 membered saturated orpartially unsaturated heterocyclic ring having 1-2 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, and a 5-6membered heteroaryl ring having 1-3 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur.

R⁶ is independently NH₂, NHR, OH, —OR, —SR, —N(R)₂

R⁷ is independently halogen, NH₂, NHR, OH, OR, SH, SR, —N(R)₂ when G isa C, and R⁷ is absent when G is N.

Each R is independently selected from the group consisting of hydrogenor an optionally substituted group selected from C₁₋₆ aliphatic, phenyl,a 3-7 membered saturated or partially unsaturated carbocyclic ring, a3-7 membered saturated or partially unsaturated monocyclic heterocyclicring having 1-2 heteroatoms independently selected from nitrogen,oxygen, or sulfur, and a 5-6 membered heteroaryl ring having 1-3heteroatoms independently selected from nitrogen, oxygen, or sulfur; or:two R groups on the same nitrogen are taken together with theirintervening atoms to form an optionally substituted 3-7 memberedsaturated, partially unsaturated, or heteroaryl ring having 1-4heteroatoms independently selected from nitrogen, oxygen, or sulfur.

A, E and G are independently N, C, CR^(a) where R^(a) is independentlyhalogen or H.

D is independently selected from N, CH, C—CN, C—NO₂, CR, C—NH₂, C—NHR,CN(R)₂, CF, CI, C—CONH₂, C—CONHR, C—CON(R)₂, C—CSN(R)₂, C—COOR,C—C(═NH)NH₂, C—OH, C—OR, C—C₁₋₄ alkylamino, C-di(C₁₋₄ alkyl)amino,C-(1,3-oxazol-2-yl), C-(1,3-thiazol-2-yl), or C-(imidazol-2-yl); Whereinalkyl is optionally substituted with one to three groups independentlyselected from halogen, amino, hydroxyl, carboxyl, or C₁₋₃ alkoxy.

D¹ is independently selected from N, CH, C—CN, C—NO₂, CR, C—NH₂, C—NHR,CN(R)₂, CF, CI, C—CONH₂, C—CONHR, C—CON(R)₂, C—CSN(R)₂, C—COOR,C—C(═NH)NH₂, C—OH, C—OR, C—C₁₋₄ alkylamino, C-di(C₁₋₄ alkyl)amino,C-(1,3-oxazol-2-yl), C-(1,3-thiazol-2-yl), or C-(imidazol-2-yl); Whereinalkyl is optionally substituted with one to three groups independentlyselected from halogen, amino, hydroxyl, carboxyl, or C₁₋₃ alkoxy.

J is independently selected from O, S, SO₂, NH or NR.

In structure II, L is independently selected from C or N; wherein when Lis N, R⁴ is absent and when L is C, R⁴ is as defined above.

W is independently O, S or NH.

X¹ and X² are independently and optionally for each occurrence an O, S,NH, NR, CH₂, CHR, C(R)₂, C═CH₂, or C═CF₂.

X³ may independently and optionally be selected from, O, NH, C═O, SO₂,C═NH, NR

Y¹ and Y² is independently and optionally for each occurrence an O, S,NH, CH₂, CF₂ or CCl₂

Z¹ and Z² are independently selected from: O⁻, S⁻, OH, SH, H, CH₃, F,BH₃ ⁻. It can be appreciated that the negative charges are balanced bypositive counter ions to form pharmaceutically acceptable salts.

Alternatively, Z¹ and Z² are independently selected from OL², OCH₂CH₂L²,OCH₂OC(O)L², OCH₂OC(O)NHL², OCH₂OC(O)N(L²)₂, OCH₂OC(O)OL², OCH₂OC(O)SL²,OCH₂NHC(O)L², OCH₂SC(O)L², OCH₂(CH₂)₁₋₆OC(O)L², OCH₂(CH₂)₁₋₆SC(O)L²,OCH₂(CH₂)₁₋₆NHC(O)L², OCH₂(CH₂)₁₋₆OC(O)OL², OCH₂(CH₂)₁₋₆SC(O)OL²,OCH₂(CH₂)₁₋₆NHC(O)OL², OCH₂O(CO)C(CH₃)₃, OCH₂O(CO)C(CH₃)₂CH₂OL²,OCH₂S(CO)C(CH₃)₂CH₂OL², OCH₂CH₂O(CO)C(CH₃)₃, OCH₂CH₂S(CO)C(CH₃)₃, OCH₂CH₂ O(CO)C(CH₃)₂CH₂OL², OCH₂ CH₂ S(CO)C(CH₃)₂CH₂OL²,OCH₂CH₂S—SCH₂(CH₂)₀₋₆L², OCH₂CH₂S—SCH₂(CH₂)₀₋₆OL², —O(CH₂CH₂O)₂₋₂₀L²,—O(CH₂CH₂O)₂₋₂₀ C(O)OL², —O(CH₂CH₂O)₂₋₂₀ C(O)NHL², —O(CH₂CH₂O)₂₋₂₀CH₂CH₂NHC(O)L², —O(CH₂CH₂O)₂₋₂₀ C(O)N(L²)₂, —S(CH₂CH₂O)₂₋₂₀L²,—S(CH₂CH₂O)₂₋₂₀ C(O)OL², —S(CH₂CH₂O)₂₋₂₀ C(O)NHL², —S(CH₂CH₂O)₂₋₂₀C(O)N(L²)₂.

Where L² is independently and optionally selected from any of thefollowing: H, N₃, C₁₋₂₀ straight chain alkyl, a C₁₋₂₀ straight chainalkenyl, C₁₋₂₀ alkynyl, C₃₋₆ cycloalkyl, C₁₋₆ haloalkyl, a tert-butyl, asubstituted tert-butyl, a glucuronide moiety, (J. Med. Chem. 1999, 42,3623-3628), a tyrosine, a tyrosine derivative, a lipid, adehydroascorbic acid derivative, a N-acetylgalactosamine derivative, aglucose derivative, a galactose derivative, a mannose derivative, afatty acid derivative, a natural peptide comprising of 2-13 amino acids,a modified peptide comprising of 2-13 amino acids, a sigma-2 receptorbinding ligand derivative, a retinoic acid derivative, a prostatespecific membrane antigen (PSMA) binding ligand derivative, a folic acidderivative, a glycirrhetinic acid (GA) receptor binding ligandderivative, an Asialo Glycoprotein Receptor (ASGPR) binding ligandderivative or a chemical derivative that allows selective uptake by acell through a preferentially expressed receptor or transporter thatexists on or exposed to the cell surface.

Synthesis of Cyclic Dinucleotides

Synthesis of cyclic dinucleotides embodied in this invention can becarried out by anyone who is skilled in the art of organic synthesis,specifically in the art of nucleoside and nucleotide synthesis,following literature procedure, amply available. For example, syntheticschemes available in Pascale Clivio, Stephanie Coantic-Castex, andDominique Guillaume, Chemical Reviews, Chem. Rev. 2013, 113, 7354-7401is given in its entirety as an example. Additionally, synthesis byBarbara L. Gaffney, Organic Letters, 2010 Jul. 16; 12(14): 3269-32712010, Barbara L. Gaffney and Roger A. Jones Curr Protoc Nucleic AcidChem. 2012 March; CHAPTER: Unit 14.8, Xu Zhang et al., Molecular Cell51, 226-235, Jul. 25, 2013 (supplementary material), Shi Min Ching etal., Bioorganic & Medicinal Chemistry 18 (2010) 6657-6665 may be used asexamples for executing synthesis of CDN molecules of the currentinvention. For brevity, following general synthesis scheme is given as ageneral example. Many modifications and alteration of reagents can beused to manipulate this general scheme, by one who is skilled in theart, to obtain desired results in terms of analogues, improvement inyield, scale up from grams to kilogram scale, environmentally friendlysynthesis and ease of synthesis.

For example, a typical phosphorothioate modified cyclic dinucleotide ofthe present invention can be prepared, by a person of the skilled art,by following the scheme outlined below.

Yet, another cyclic dinucleotide of the present invention can beprepared, by a person skilled in the art, by following the schemeoutlined below

All the compositions and methods disclosed and claimed herein can bemade and executed without undue experimentation in light of the presentdisclosure. While the compositions and methods of this invention havebeen described in terms of preferred embodiments, it will be apparent tothose of skill in the art that variations may be applied to thecompositions and methods described herein without departing from theconcept, spirit and scope of the invention. Such variations are intendedto fall within the scope of the appended claims.

What is claimed is:
 1. A compound of formula I

wherein, B¹ and B² are selected from a group consisting of

Wherein, each R³, R⁴, R⁵, R⁸, R⁹, R¹⁰, R¹¹ and R¹² is selected from agroup consisting of hydrogen, halogen, —NO₂, —CN, R, —OR, —SR, —NHR,—N(R)₂, —C(O)R, —CO₂R, —C(O)C(O)R, —C(O)CH₂C(O)R, —S(O)R, —S(O)₂R,—C(O)N(R)₂, —SO₂N(R)₂, —OC(O)R, —N(R)C(O)R, —N(R)C(═NR)N(R)₂,—C(═NR)N(R)₂, —C═NOR, —N(R)SO₂N(R)₂, —N(R)SO₂R, —OC(O)N(R)₂, and R⁶ isselected from a group consisting of NH₂, NHR, OH, —OR, —SR, —N(R)₂, R⁷is selected from a group consisting of NH₂, NHR, OH, OR, SH, SR, —N(R)₂when G is a C, and R⁷ is absent when G is N, Each R is independentlyselected from a group consisting of hydrogen, C₁₋₆ aliphatic, phenyl, a3-7 membered saturated, partially unsaturated carbocyclic ring, A, E andG are selected from a group consisting of N, C, CR^(a) where R^(a) isindependently a halogen or H, D is selected from a group consisting ofN, CH, C—CN, C—NO₂, CR, C—NH₂, C—NHR, CN(R)₂, CF, CI, C—CONH₂, C—CONHR,C—CON(R)₂, C—CSN(R)₂, C—COOR, C—C(═NH)NH₂, C—OH, C—OR, C—C₁₋₄alkylamino, C-di(C₁₋₄ alkyl)amino, C-(1,3-oxazol-2-yl),C-(1,3-thiazol-2-yl), or C-(imidazol-2-yl); wherein alkyl is optionallysubstituted with one to three groups selected from a group consisting ofhalogen, amino, hydroxyl, carboxyl, or C₁₋₃ alkoxy, D¹ is selected froma group consisting of N, CH, C—CN, C—NO₂, CR, C—NH₂, C—NHR, CN(R)₂, CF,CI, C—CONH₂, C—CONHR, C—CON(R)₂, C—CSN(R)₂, C—COOR, C—C(═NH)NH₂, C—OH,C—OR, C—C₁₋₄ alkylamino, C-di(C₁₋₄ alkyl)amino, C-(1,3-oxazol-2-yl),C-(1,3-thiazol-2-yl), or C-(imidazol-2-yl); wherein alkyl is optionallysubstituted with one to three groups independently selected from a groupconsisting of halogen, amino, hydroxyl, carboxyl, C₁₋₃ alkoxy, J isselected from a group consisting of O, S, SO₂, NH, NR, L is selectedfrom a group consisting of C, N; wherein when L is N, R⁴ is absent andwhen L is C, R⁴ is as defined above, W is selected from a groupconsisting of O, S, NH, R¹ and R² are independently and optionallyselected from a group consisting of hydrogen, halogen, —NO₂, —CN, —OR,—SR, —NHR, —N(R)₂, —C(O)R, —CO₂R, —C(O)CH₂C(O)R, —S(O)R, —S(O)₂R,—C(O)N(R)₂, —SO₂N(R)₂, —OC(O)R, —N(R)C(O)R, —N(R)N(R)₂,—N(R)C(═NR)N(R)₂, C(═NR)N(R)₂, —C═NOR, —N(R)C(O)N(R)₂, —N(R)SO₂N(R)₂,—N(R)SO₂R, —OC(O)N(R)₂, and optionally substituted C₁₋₁₂ aliphatic orC₁₋₄ alkoxy-C₁₋₄ alkyl; R¹ and R² cannot be the same except forhydrogen, Either B_(L1) or B_(L2) is independently and optionally a bondconnecting the two carbons attached to each of them, Either B_(L1) orB_(L2) are independently absent or both B_(L1) and B_(L2) may be absentsuch that no C—C bond exists, Both B_(L1) and B_(L2) cannot be a bond atthe same time, Each R^(1′) is selected from a group consisting ofhydrogen, halogen, N₃, C(O)OH, CN, C(O)NH₂, C(S)NH₂, C(O)OR, R, X¹ andX² are selected from a group consisting of O, S, NH, NR, CH₂, CHR,C(R)₂, C═CH₂, C═CF₂, X³ is selected from a group consisting of O, NH,C═O, SO₂, C═NH, NR, Y¹ and Y² are selected from a group consisting of O,S, NH, CH₂, CF₂ or CCl₂ Z¹ and Z² are selected from a group consistingof O⁻, S⁻, OH, SH, H, CH₃, F, BH₃ ⁻, Alternatively, Z¹ and Z² areselected from a group consisting of OL², OCH₂CH₂L², OCH₂OC(O)L²,OCH₂OC(O)NHL², OCH₂OC(O)N(L²)₂, OCH₂OC(O)OL², OCH₂OC(O)SL²,OCH₂NHC(O)L², OCH₂SC(O)L², OCH₂(CH₂)₁₋₆OC(O)L², OCH₂(CH₂)₁₋₆SC(O)L²,OCH₂(CH₂)₁₋₆NHC(O)L², OCH₂(CH₂)₁₋₆OC(O)OL², OCH₂(CH₂)₁₋₆SC(O)OL²,OCH₂(CH₂)₁₋₆NHC(O)OL², OCH₂O(CO)C(CH₃)₃, OCH₂O(CO)C(CH₃)₂CH₂OL²,OCH₂S(CO)C(CH₃)₂CH₂OL², OCH₂CH₂O(CO)C(CH₃)₃, OCH₂CH₂S(CO)C(CH₃)₃, OCH₂CH₂ O(CO)C(CH₃)₂CH₂OL², OCH₂ CH₂ S(CO)C(CH₃)₂CH₂OL²,OCH₂CH₂S—SCH₂(CH₂)₀₋₆L², OCH₂CH₂S—SCH₂(CH₂)₀₋₆OL², —O(CH₂CH₂O)₂₋₂₀L²,—O(CH₂CH₂O)₂₋₂₀ C(O)OL², O(CH₂CH₂O)₂₋₂₀ C(O)NHL², —O(CH₂CH₂O)₂₋₂₀CH₂CH₂NHC(O)L², —O(CH₂CH₂O)₂₋₂₀ C(O)N(L²)₂, —S(CH₂CH₂O)₂₋₂₀L²,—S(CH₂CH₂O)₂₋₂₀ C(O)OL², —S(CH₂CH₂O)₂₋₂₀ C(O)NHL², S(CH₂CH₂O)₂₋₂₀C(O)N(L²)₂, where L² is independently selected from a group consistingof H, N₃, C₁₋₂₀ straight chain alkyl, a C₁₋₂₀ straight chain alkenyl,C₁₋₂₀ alkynyl, C₃₋₆ cycloalkyl, C₁₋₆ haloalkyl, a tert-butyl, asubstituted tert-butyl, a glucuronide moiety, a tyrosine.
 2. Thecompound according to claim 1, wherein, B¹ and B² are independentlyselected from a group consisting of,

wherein, each R³, R⁴ and R⁵ are independently and optionally selectedfrom a group consisting of hydrogen, halogen, —NO₂, —CN, R, —OR, —SR,—NHR, —N(R)₂, —C(O)R, —CO₂R, —C(O)C(O)R, —C(O)CH₂C(O)R, —S(O)R, —S(O)₂R,—C(O)N(R)₂, —SO₂N(R)₂, —OC(O)R, —N(R)C(O)R, —N(R)C(═NR)N(R)₂,—C(═NR)N(R)₂, —C═NOR, —N(R)SO₂N(R)₂, —N(R)SO₂R, —OC(O)N(R)₂, C₁₋₁₂aliphatic, phenyl, each R is independently selected from the groupconsisting of hydrogen, C₁₋₆ aliphatic, phenyl, R¹ and R² areindependently and optionally selected from the group consisting ofhydrogen, halogen, OH, —NO₂, —CN, —OR, —SR, —NHR, —N(R)₂, —C(O)R, —CO₂R,—C(O)CH₂C(O)R, —S(O)R, —S(O)₂R, —C(O)N(R)₂, —SO₂N(R)₂, —OC(O)R,—N(R)C(O)R, —N(R)N(R)₂, —N(R)C(═NR)N(R)₂, —C(═NR)N(R)₂, —C═NOR,—N(R)C(O)N(R)₂, —N(R)SO₂N(R)₂, —N(R)SO₂R, —OC(O)N(R)₂, optionallysubstituted C₁₋₁₂ aliphatic, C₁₋₄ alkoxy, —C₁₋₄ alkyl; R¹ and R² cannotbe the same except for hydrogen, either B_(L1) or B_(L2) isindependently and optionally a bond connecting the two carbons attachedto each of them, either B_(L1) or B_(L2) may be optionally absent orboth B_(L1) and B_(L2) may be absent such that no C—C bond exists, bothB_(L1) and B_(L2) cannot be a bond at the same time, each R^(1′) isindependently and optionally selected from a group consisting ofhydrogen, halogen, OH, N₃, C(O)OH, CN, C(O)NH₂, C(S)NH₂, C(O)OR, R, X¹and X² are selected from a group consisting of O, S, NH, NR, CH₂, CHR,C(R)₂, C═CH₂, C═CF₂ Y¹ and Y² are selected from a group consisting of O,S, NH, CH₂, CF₂, CCl₂, Z¹ and Z² are selected from a group consisting ofO, S, OH, SH, H, CH₃, F, BH₃ ⁻, alternatively, Z¹ and Z² are selectedfrom a group consisting of OL², OCH₂CH₂L², OCH₂OC(O)L², OCH₂OC(O)NHL²,OCH₂OC(O)N(L²)₂, OCH₂OC(O)OL², OCH₂OC(O)SL², OCH₂NHC(O)L², OCH₂SC(O)L²,OCH₂(CH₂)₁₋₆OC(O)L², OCH₂(CH₂)₁₋₆SC(O)L², OCH₂(CH₂)₁₋₆NHC(O)L²,OCH₂(CH₂)₁₋₆OC(O)OL², OCH₂(CH₂)₁₋₆SC(O)OL², OCH₂(CH₂)₁₋₆NHC(O)OL²,OCH₂O(CO)C(CH₃)₃, OCH₂O(CO)C(CH₃)₂CH₂OL², OCH₂S(CO)C(CH₃)₂CH₂OL²,OCH₂CH₂O(CO)C(CH₃)₃, OCH₂CH₂S(CO)C(CH₃)₃, OCH₂ CH₂ O(CO)C(CH₃)₂CH₂OL²,OCH₂ CH₂ S(CO)C(CH₃)₂CH₂OL², OCH₂CH₂S—SCH₂(CH₂)₀₋₆L²,OCH₂CH₂S—SCH₂(CH₂)₀₋₆OL², —O(CH₂CH₂O)₂₋₂₀L², —O(CH₂CH₂O)₂₋₂₀ C(O)OL²,—O(CH₂CH₂O)₂₋₂₀ C(O)NHL², —O(CH₂CH₂O)₂₋₂₀ CH₂CH₂NHC(O)L²,—O(CH₂CH₂O)₂₋₂₀ C(O)N(L²)₂, —S(CH₂CH₂O)₂₋₂₀L², —S(CH₂CH₂O)₂₋₂₀ C(O)OL²,—S(CH₂CH₂O)₂₋₂₀ C(O)NHL², —S(CH₂CH₂O)₂₋₂₀ C(O)N(L²)₂, where L² isindependently selected from a group consisting of H, N₃, C₁₋₂₀ straightchain alkyl, a C₁₋₂₀ straight chain alkenyl, C₁₋₂₀ alkynyl, C₃₋₆cycloalkyl, C₁₋₆ haloalkyl, a tert-butyl, a substituted tert-butyl, atyrosine.
 3. The compound according to claim 1, wherein the compound offormula I is a compound of formula I(a),

wherein, B¹ and B² are independently selected from a group consisting of

wherein, each R³, R⁴, R⁵, R⁸, R⁹, R¹⁰, R¹¹ and R¹² is independently andoptionally selected from a group consisting of hydrogen, halogen, —NO₂,—CN, R, —OR, —SR, —NHR, —N(R)₂, —C(O)R, —C0₂R, —C(O)C(O)R,—C(O)CH₂C(O)R, —S(O)R, —S(O)₂R, —C(O)N(R)₂, —SO₂N(R)₂, —OC(O)R,—N(R)C(O)R, —N(R)C(═NR)N(R)₂, —C(═NR)N(R)₂, —C═NOR, —N(R)SO₂N(R)₂,—N(R)SO₂R, —OC(O)N(R)₂, C₁₋₁₂ aliphatic, phenyl, R⁶ is selected from agroup consisting of NH₂, NHR, OH, —OR, —SR, —N(R)₂, R⁷ is selected froma group consisting of halogen, NH₂, NHR, OH, OR, SH, SR, —N(R)₂ when Gis a C, and R⁷ is absent when G is N, each R is independently selectedfrom the group consisting of hydrogen, C₁₋₆ aliphatic, phenyl, A, E andG are selected from a group consisting of N, C, CR^(a) where R^(a) isindependently a halogen or H, D is selected from a group consisting ofN, CH, C—CN, C—NO₂, CR, C—NH₂, C—NHR, CN(R)₂, CF, CI, C—CONH₂, C—CONHR,C—CON(R)₂, C—CSN(R)₂, C—COOR, C—C(═NH)NH₂, C—OH, C—OR, C—C₁₋₄alkylamino, C-di(C₁₋₄ alkyl)amino, C-(1,3-oxazol-2-yl),C-(1,3-thiazol-2-yl), C-(imidazol-2-yl); D¹ is selected from a groupconsisting of N, CH, C—CN, C—NO₂, CR, C—NH₂, C—NHR, CN(R)₂, CF, CI,C—CONH₂, C—CONHR, C—CON(R)₂, C—CSN(R)₂, C—COOR, C—C(═NH)NH₂, C—OH, C—OR,C—C₁₋₄ alkylamino, C-di(C₁₋₄ alkyl)amino, C-(1,3-oxazol-2-yl),C-(1,3-thiazol-2-yl), C-(imidazol-2-yl); J is selected from a groupconsisting of O, S, SO₂, NH, NR, L is selected from a group consistingof C, N; wherein when L is N, R⁴ is absent and when L is C, R⁴ is asdefined above, W is independently selected from a group consisting of O,S, NH, R¹ and R² are independently and optionally selected from a groupconsisting of hydrogen, halogen, OH, —NO₂, —CN, —OR, —SR, —NHR, —N(R)₂,—C(O)R, —CO₂R, —C(O)CH₂C(O)R, —S(O)R, — S(O)₂R, —C(O)N(R)₂, —SO₂N(R)₂,—OC(O)R, —N(R)C(O)R, —N(R)N(R)₂, —N(R)C(═NR)N(R)₂, —C(═NR)N(R)₂, —C═NOR,—N(R)C(O)N(R)₂, —N(R)SO₂N(R)₂, —N(R)SO₂R, —OC(O)N(R)₂, C₁₋₁₂ aliphatic,C₁₋₄ alkoxy-C₁₋₄ alkyl, R¹ and R² cannot be the same except forhydrogen, B_(L2) is a bond connecting the two carbons attached to it oroptionally not a bond, X³ is selected from a group consisting of O, NH,C═O, SO₂, C═NH, NR, Z¹ and Z² are selected from a group consisting ofO⁻, S⁻, OH, SH, H, CH₃, F, BH₃ ⁻, Alternatively, Z¹ and Z² are selectedfrom a group consisting of OL², OCH₂CH₂L², OCH₂OC(O)L², OCH₂OC(O)NHL²,OCH₂OC(O)N(L²)₂, OCH₂OC(O)OL², OCH₂OC(O)SL², OCH₂NHC(O)L², OCH₂SC(O)L²,OCH₂(CH₂)₁₋₆OC(O)L², OCH₂(CH₂)₁₋₆SC(O)L², OCH₂(CH₂)₁₋₆NHC(O)L²,OCH₂(CH₂)₁₋₆OC(O)OL², OCH₂(CH₂)₁₋₆SC(O)OL², OCH₂(CH₂)₁₋₆NHC(O)OL²,OCH₂O(CO)C(CH₃)₃, OCH₂O(CO)C(CH₃)₂CH₂OL², OCH₂S(CO)C(CH₃)₂CH₂OL²,OCH₂CH₂O(CO)C(CH₃)₃, OCH₂CH₂S(CO)C(CH₃)₃, OCH₂ CH₂ O(CO)C(CH₃)₂CH₂OL²,OCH₂ CH₂ S(CO)C(CH₃)₂CH₂OL², OCH₂CH₂S—SCH₂(CH₂)₀₋₆L²,OCH₂CH₂S—SCH₂(CH₂)₀₋₆OL², —O(CH₂CH₂O)₂₋₂₀L², —O(CH₂CH₂O)₂₋₂₀ C(O)OL²,O(CH₂CH₂O)₂₋₂₀ C(O)NHL², —O(CH₂CH₂O)₂₋₂₀ CH₂CH₂NHC(O)L², —O(CH₂CH₂O)₂₋₂₀C(O)N(L²)₂, —S(CH₂CH₂O)₂₋₂₀L², —S(CH₂CH₂O)₂₋₂₀ C(O)OL², —S(CH₂CH₂O)₂₋₂₀C(O)NHL², S(CH₂CH₂O)₂₋₂₀, C(O)N(L²)₂, where L² is independently andoptionally selected from a group consisting of H, N₃, C₁₋₂₀ straightchain alkyl, a C₁₋₂₀ straight chain alkenyl, C₁₋₂₀ alkynyl, C₃₋₆cycloalkyl, C₁₋₆ haloalkyl, a tert-butyl, a substituted tert-butyl, atyrosine.
 4. The compound according to claim 1, wherein the compound offormula I is a compound of formula I(b),

wherein, B¹ and B² are independently selected from a group consisting of

wherein, each R³, R⁴, R⁵, R⁸, R⁹, R¹⁰, R¹¹ and R¹² is independently andoptionally selected from a group consisting of hydrogen, halogen, —NO₂,—CN, R, —OR, —SR, —NHR, —N(R)₂, —C(O)R, —CO₂R, —C(O)C(O)R,—C(O)CH₂C(O)R, —S(O)R, —S(O)₂R, —C(O)N(R)₂, —SO₂N(R)₂, —OC(O)R,—N(R)C(O)R, —N(R)C(═NR)N(R)₂, —C(═NR)N(R)₂, —C═NOR, —N(R)SO₂N(R)₂,—N(R)SO₂R, —OC(O)N(R)₂, an optionally substituted group selected fromC₁₋₁₂ aliphatic, phenyl, R⁶ is selected from a group consisting of NH₂,NHR, OH, —OR, —SR, —N(R)₂, R⁷ is selected from a group consisting ofhalogen, NH₂, NHR, OH, OR, SH, SR, —N(R)₂, when G is a C, and R⁷ isabsent when G is N, each R is independently selected from the groupconsisting of hydrogen, C₁₋₆ aliphatic, phenyl, A, E and G are selectedfrom a group consisting of N, C, CR^(a), where R^(a) is independently ahalogen or H, D is selected from a group consisting of N, CH, C—CN,C—NO₂, CR, C—NH₂, C—NHR, CN(R)₂, CF, CI, C—CONH₂, C—CONHR, C—CON(R)₂,C—CSN(R)₂, C—COOR, C—C(═NH)NH₂, C—OH, C—OR, C—C₁₋₄ alkylamino, C-di(C₁₋₄alkyl)amino, C-(1,3-oxazol-2-yl), C-(1,3-thiazol-2-yl),C-(imidazol-2-yl), D¹ is selected from a group consisting of N, CH,C—CN, C—NO₂, CR, C—NH₂, C—NHR, CN(R)₂, CF, CI, C—CONH₂, C—CONHR,C—CON(R)₂, C—CSN(R)₂, C—COOR, C—C(═NH)NH₂, C—OH, C—OR, C—C₁₋₄alkylamino, C-di(C₁₋₄ alkyl)amino, C-(1,3-oxazol-2-yl),C-(1,3-thiazol-2-yl), C-(imidazol-2-yl), J is selected from a groupconsisting of O, S, SO₂, NH, NR, L is selected from a group consistingof C, N; wherein when L is N, R⁴ is absent and when L is C, R⁴ is asdefined above, W is selected from a group consisting of O, S, NH, R¹ isindependently and optionally selected from the group consisting ofhydrogen, halogen, OH, —NO₂, —CN, —OR, —SR, —NHR, —N(R)₂, —C(O)R, —CO₂R,—C(O)CH₂C(O)R, —S(O)R, —S(O)₂R, —C(O)N(R)₂, —SO₂N(R)₂, —OC(O)R,—N(R)C(O)R, —N(R)N(R)₂, —N(R)C(═NR)N(R)₂, C(═NR)N(R)₂, —C═NOR,—N(R)C(O)N(R)₂, —N(R)SO₂N(R)₂, —N(R)SO₂R, —OC(O)N(R)₂, C₁₋₁₂ aliphaticor C₁₋₄ alkoxy-C₁₋₄ alkyl, X³ is selected from a group consisting of O,NH, C═O, SO₂, C═NH, NR Z¹ and Z² are selected from a group consisting ofO⁻, S⁻, OH, SH, H, CH₃, F, BH₃ ⁻, alternatively, Z¹ and Z² are selectedfrom a group consisting of OL², OCH₂CH₂L², OCH₂OC(O)L², OCH₂OC(O)NHL²,OCH₂OC(O)N(L²)₂, OCH₂OC(O)OL², OCH₂OC(O)SL², OCH₂NHC(O)L², OCH₂SC(O)L²,OCH₂(CH₂)₁₋₆OC(O)L², OCH₂(CH₂)₁₋₆SC(O)L², OCH₂(CH₂)₁₋₆NHC(O)L²,OCH₂(CH₂)₁₋₆OC(O)OL², OCH₂(CH₂)₁₋₆SC(O)OL², OCH₂(CH₂)₁₋₆NHC(O)OL²,OCH₂O(CO)C(CH₃)₃, OCH₂O(CO)C(CH₃)₂CH₂OL², OCH₂S(CO)C(CH₃)₂CH₂OL²,OCH₂CH₂O(CO)C(CH₃)₃, OCH₂CH₂S(CO)C(CH₃)₃, OCH₂ CH₂ O(CO)C(CH₃)₂CH₂OL²,OCH₂ CH₂ S(CO)C(CH₃)₂CH₂OL², OCH₂CH₂S—SCH₂(CH₂)₀₋₆L²,OCH₂CH₂S—SCH₂(CH₂)₀₋₆OL², O(CH₂CH₂O)₂₋₂₀L², —O(CH₂CH₂O)₂₋₂₀ C(O)OL²,—O(CH₂CH₂O)₂₋₂₀ C(O)NHL², —O(CH₂CH₂O)₂₋₂₀ CH₂CH₂NHC(O)L²,—O(CH₂CH₂O)₂₋₂₀ C(O)N(L²)₂, —S(CH₂CH₂O)₂₋₂₀L², —S(CH₂CH₂O)₂₋₂₀ C(O)OL²,—S(CH₂CH₂O)₂₋₂₀ C(O)NHL², —S(CH₂CH₂O)₂₋₂₀ C(O)N(L²)₂, where L² isindependently and optionally selected from a group consisting of H, N₃,C₁₋₂₀ straight chain alkyl, a C₁₋₂₀ straight chain alkenyl, C₁₋₂₀alkynyl, C₃₋₆ cycloalkyl, C₁₋₆ haloalkyl, a tert-butyl, a substitutedtert-butyl, a tyrosine.
 5. The compound according to claim 1, whereinthe compound of formula I is a compound of formula I(c),

wherein, B¹ and B² are independently selected from a group consisting of

wherein, each R³, R⁴, R⁵, R⁸, R⁹, R¹⁰, R¹¹ and R¹² is independently andoptionally selected from a group consisting of hydrogen, halogen, —NO₂,—CN, R, —OR, —SR, —NHR, —N(R)₂, —C(O)R, —CO₂R, —C(O)C(O)R,—C(O)CH₂C(O)R, —S(O)R, —S(O)₂R, —C(O)N(R)₂, —SO₂N(R)₂, —OC(O)R,—N(R)C(O)R, —N(R)C(═NR)N(R)₂, —C(═NR)N(R)₂, —C═NOR, —N(R)SO₂N(R)₂,—N(R)SO₂R, —OC(O)N(R)₂, C₁₋₁₂ aliphatic, phenyl, R⁶ is independentlyNH₂, NHR, OH, —OR, —SR, —N(R)₂, R⁷ is selected from a group consistingof NH₂, NHR, OH, OR, SH, SR, —N(R)₂ when G is a C, and R⁷ is absent whenG is N, each R is independently selected from the group consisting ofhydrogen, C₁₋₆ aliphatic, phenyl, A, E and G are selected from a groupconsisting of N, C, CR^(a) where R^(a) is independently a halogen or H,D is selected from a group consisting of N, CH, C—CN, C—NO₂, CR, C—NH₂,C—NHR, CN(R)₂, CF, CI, C—CONH₂, C—CONHR, C—CON(R)₂, C—CSN(R)₂, C—COOR,C—C(═NH)NH₂, C—OH, C—OR, C—C₁₋₄ alkylamino, C-di(C₁₋₄ alkyl)amino,C-(1,3-oxazol-2-yl), C-(1,3-thiazol-2-yl), C-(imidazol-2-yl); whereinalkyl is optionally substituted with one to three groups selected from agroup consisting of halogen, amino, hydroxyl, carboxyl, C₁₋₃ alkoxy, D¹is selected from a group consisting of N, CH, C—CN, C—NO₂, CR, C—NH₂,C—NHR, CN(R)₂, CF, CI, C—CONH₂, C—CONHR, C—CON(R)₂, C—CSN(R)₂, C—COOR,C—C(═NH)NH₂, C—OH, C—OR, C—C₁₋₄ alkylamino, C-di(C₁₋₄ alkyl)amino,C-(1,3-oxazol-2-yl), C-(1,3-thiazol-2-yl), C-(imidazol-2-yl), J isindependently selected from a group consisting of O, S, SO₂, NH, NR, Lis selected from a group consisting of C, N; wherein when L is N, R⁴ isabsent and when L is C, R⁴ is as defined above, W is independentlyselected from a group consisting of O, S, NH, R¹ and R² areindependently and optionally selected from a group consisting ofhydrogen, halogen, OH, —NO₂, —CN, —OR, —SR, —NHR, —N(R)₂, —C(O)R, —CO₂R,—C(O)CH₂C(O)R, —S(O)R, —S(O)₂R, —C(O)N(R)₂, —SO₂N(R)₂, —OC(O)R,—N(R)C(O)R, —N(R)N(R)₂, —N(R)C(═NR)N(R)₂, —C(═NR)N(R)₂, —C═NOR,—N(R)C(O)N(R)₂, —N(R)SO₂N(R)₂, —N(R)SO₂R, —OC(O)N(R)₂, and optionallysubstituted with C₁₋₁₂ aliphatic or C₁₋₄ alkoxy-C₁₋₄ alkyl, R¹ and R²cannot be the same except for hydrogen, X³ is selected from a groupconsisting of O, NH, C═O, SO₂, C═NH, NR, Z¹ and Z² are selected from agroup consisting of O⁻, S⁻, OH, SH, H, CH₃, F, BH₃ ⁻, Alternatively, Z¹and Z² are selected from a group consisting of OL², OCH₂CH₂L²,OCH₂OC(O)L², OCH₂OC(O)NHL², OCH₂OC(O)N(L²)₂, OCH₂OC(O)OL², OCH₂OC(O)SL²,OCH₂NHC(O)L², OCH₂SC(O)L², OCH₂(CH₂)₁₋₆OC(O)L², OCH₂(CH₂)₁₋₆SC(O)L²,OCH₂(CH₂)₁₋₆NHC(O)L², OCH₂(CH₂)₁₋₆OC(O)OL², OCH₂(CH₂)₁₋₆SC(O)OL²,OCH₂(CH₂)₁₋₆NHC(O)OL², OCH₂O(CO)C(CH₃)₃, OCH₂O(CO)C(CH₃)₂CH₂OL²,OCH₂S(CO)C(CH₃)₂CH₂OL², OCH₂CH₂O(CO)C(CH₃)₃, OCH₂CH₂S(CO)C(CH₃)₃, OCH₂CH₂ O(CO)C(CH₃)₂CH₂OL², OCH₂ CH₂ S(CO)C(CH₃)₂CH₂OL²,OCH₂CH₂S—SCH₂(CH₂)₀₋₆L², OCH₂CH₂S—SCH₂(CH₂)₀₋₆OL², —O(CH₂CH₂O)₂₋₂₀L²,—O(CH₂CH₂O)₂₋₂₀ C(O)OL², O(CH₂CH₂O)₂₋₂₀ C(O)NHL², —O(CH₂CH₂O)₂₋₂₀CH₂CH₂NHC(O)L², —O(CH₂CH₂O)₂₋₂₀ C(O)N(L²)₂, —S(CH₂CH₂O)₂₋₂₀L²,—S(CH₂CH₂O)₂₋₂₀ C(O)OL², —S(CH₂CH₂O)₂₋₂₀ C(O)NHL², —S(CH₂CH₂O)₂₋₂₀C(O)N(L²)₂, where L² is independently and optionally selected from agroup consisting of H, N₃, C₁₋₂₀ straight chain alkyl, a C₁₋₂₀ straightchain alkenyl, C₁₋₂₀ alkynyl, C₃₋₆ cycloalkyl, C₁₋₆ haloalkyl, atert-butyl, a substituted tert-butyl, a glucuronide moiety, a tyrosine.6. A pharmaceutical composition, said pharmaceutical compositioncomprising: a. the compound according to claim 1, b. A pharmaceuticallyacceptable carrier.
 7. A method for activating immune response against atarget antigen in a subject, comprising administering concurrently tothe subject a therapeutically effective dose of the compound accordingclaim 1 and an antigen that corresponds to at least a portion of thetarget antigen, wherein the compound and the antigen are in particulateform.
 8. A method for inducing STING-dependent type 1 interferonproduction in a subject, comprising: administering a compositionaccording claim 1 to the subject in an amount sufficient to induceSTING-dependent type 1 interferon production.
 9. A method of inhibitingSTING-dependent type 1 interferon production in a subject in needthereof, comprising: administering a composition according to claim 1 tothe subject in an amount sufficient to inhibit STING-dependent type 1interferon production.
 10. A compound of formula I′

wherein: B¹ and B² are independently and optionally selected from agroup consisting of:

each R¹ and R² are independently and optionally selected from a groupconsisting of hydrogen, halogen, —NO₂, —CN, —OR, —SR, —NHR, —N(R)₂,—C(O)R, —CO₂R, —C(O)CH₂C(O)R, —S(O)R, —S(O)₂R, —C(O)N(R)₂, —SO₂N(R)₂,—OC(O)R, —N(R)C(O)R, —N(R)N(R)₂, —N(R)C(═NR)N(R)₂, —C(═NR)N(R)₂, —C═NOR,—N(R)C(O)N(R)₂, —N(R)SO₂N(R)₂, —N(R)SO₂R, —OC(O)N(R)₂, and optionallysubstituted with C₁₋₁₂ aliphatic or C₁₋₄ alkoxy-C₁₋₄ alkyl, R¹ and R²cannot be the same except for hydrogen, B_(L2) is a bond connecting thetwo carbons attached to it or optionally not a bond, Each R^(1′) areindependently and optionally selected from a group consisting ofhydrogen, halogen, N₃, C(O)OH, CN, C(O)NH₂, C(S)NH₂, C(O)OR, R, each R³,R⁴, R⁵, R⁸, R⁹, R¹⁰, R¹¹ and R¹² is independently and optionallyselected from a group consisting of hydrogen, halogen, —NO₂, —CN, R,—OR, —SR, —NHR, —N(R)₂, —C(O)R, —CO₂R, —C(O)C(O)R, —C(O)CH₂C(O)R,—S(O)R, —S(O)₂R, —C(O)N(R)₂, —SO₂N(R)₂, —OC(O)R, —N(R)C(O)R,—N(R)C(═NR)N(R)₂, —C(═NR)N(R)₂, —C═NOR, —N(R)SO₂N(R)₂, —N(R)SO₂R,—OC(O)N(R)₂, C₁₋₁₂ aliphatic, phenyl, R⁶ is independently selected froma group consisting of NH₂, NHR, OH, —OR, —SR, —N(R)₂, R⁷ isindependently selected from a group consisting of halogen, NH₂, NHR, OH,OR, SH, SR, —N(R)₂ when G is a C, and R⁷ is absent when G is N, each Ris independently selected from the group consisting of hydrogen, C₁₋₆aliphatic, phenyl, A, E and G are independently selected from a groupconsisting of N, C, CR^(a) where R^(a) is independently halogen or H, Dis independently selected from a group consisting of N, CH, C—CN, C—NO₂,CR, C—NH₂, C—NHR, CN(R)₂, CF, CI, C—CONH₂, C—CONHR, C—CON(R)₂,C—CSN(R)₂, C—COOR, C—C(═NH)NH₂, C—OH, C—OR, C—C₁₋₄ alkylamino, C-di(C₁₋₄alkyl)amino, C-(1,3-oxazol-2-yl), C-(1,3-thiazol-2-yl), orC-(imidazol-2-yl), D¹ is independently selected from a group consistingof N, CH, C—CN, C—NO₂, CR, C—NH₂, C—NHR, CN(R)₂, CF, CI, C—CONH₂,C—CONHR, C—CON(R)₂, C—CSN(R)₂, C—COOR, C—C(═NH)NH₂, C—OH, C—OR, C—C₁₋₄alkylamino, C-di(C₁₋₄ alkyl)amino, C-(1,3-oxazol-2-yl),C-(1,3-thiazol-2-yl), C-(imidazol-2-yl); wherein alkyl is optionallysubstituted with one to three groups independently selected from a groupconsisting of halogen, amino, hydroxyl, carboxyl, or C₁₋₃ alkoxy, J isindependently selected from a group consisting of O, S, SO₂, NH, NR, Instructure II, L is independently C or N; wherein when L is N, R⁴ isabsent and when L is C, R⁴ is as defined above, W is independentlyselected from a group consisting of O, S, NH, X¹ and X² areindependently selected from a group consisting of O, S, NH, NR, CH₂,CHR, C(R)₂, C═CH₂, C═CF₂, X³ is selected from a group consisting of O,NH, C═O, SO₂, C═NH, NR, Y¹ and Y² are selected from a group consistingof O, S, NH, CH₂, CF₂, CCl₂, Z¹ and Z² are independently selected from agroup consisting of O⁻, S⁻, OH, SH, H, CH₃, F, BH₃ ⁻, alternatively, Z¹and Z² are independently selected from a group consisting of OL²,OCH₂CH₂L², OCH₂OC(O)L², OCH₂OC(O)NHL², OCH₂OC(O)N(L²)₂, OCH₂OC(O)OL²,OCH₂OC(O)SL², OCH₂NHC(O)L², OCH₂SC(O)L², OCH₂(CH₂)₁₋₆OC(O)L²,OCH₂(CH₂)₁₋₆SC(O)L², OCH₂(CH₂)₁₋₆NHC(O)L², OCH₂(CH₂)₁₋₆OC(O)OL²,OCH₂(CH₂)₁₋₆SC(O)OL², OCH₂(CH₂)₁₋₆NHC(O)OL², OCH₂O(CO)C(CH₃)₃,OCH₂O(CO)C(CH₃)₂CH₂OL², OCH₂S(CO)C(CH₃)₂CH₂OL², OCH₂CH₂O(CO)C(CH₃)₃,OCH₂CH₂S(CO)C(CH₃)₃, OCH₂ CH₂ O(CO)C(CH₃)₂CH₂OL², OCH₂ CH₂S(CO)C(CH₃)₂CH₂OL², OCH₂CH₂S—SCH₂(CH₂)₀₋₆L², OCH₂CH₂S—SCH₂(CH₂)₀₋₆OL²,—O(CH₂CH₂O)₂₋₂₀L², —O(CH₂CH₂O)₂₋₂₀ C(O)OL², O(CH₂CH₂O)₂₋₂₀ C(O)NHL²,—O(CH₂CH₂O)₂₋₂₀ CH₂CH₂NHC(O)L², —O(CH₂CH₂O)₂₋₂₀ C(O)N(L²)₂,—S(CH₂CH₂O)₂₋₂₀L², —S(CH₂CH₂O)₂₋₂₀ C(O)OL², —S(CH₂CH₂O)₂₋₂₀ C(O)NHL²,S(CH₂CH₂O)₂₋₂₀ C(O)N(L²)₂, where L² is independently and optionallyselected from a group consisting of H, N₃, C₁₋₂₀ straight chain alkyl, aC₁₋₂₀ straight chain alkenyl, C₁₋₂₀ alkynyl, C₃₋₆ cycloalkyl, C₁₋₆haloalkyl, a tert-butyl, a substituted tert-butyl, a tyrosine.
 11. Thecompound according to claim 10, wherein, B¹ and B² are independentlyselected from a group consisting of,

wherein, each R³, R⁴ and R⁵ is independently and optionally selectedfrom a group consisting of hydrogen, halogen, —NO₂, —CN, R, —OR, —SR,—NHR, —N(R)₂, —C(O)R, —CO₂R, —C(O)C(O)R, —C(O)CH₂C(O)R, —S(O)R, —S(O)₂R,—C(O)N(R)₂, —SO₂N(R)₂, —OC(O)R, —N(R)C(O)R, —N(R)C(═NR)N(R)₂,—C(═NR)N(R)₂, —C═NOR, —N(R)SO₂N(R)₂, —N(R)SO₂R, —OC(O)N(R)₂, C₁₋₁₂aliphatic, phenyl, each R is independently selected from a groupconsisting of hydrogen, an optionally substituted group selected fromC₁₋₆ aliphatic, phenyl, R¹ and R² are independently and optionallyselected from a group consisting of hydrogen, halogen, OH, —NO₂, —CN,—OR, —SR, —NHR, —N(R)₂, —C(O)R, —CO₂R, —C(O)CH₂C(O)R, —S(O)R, —S(O)₂R,—C(O)N(R)₂, —SO₂N(R)₂, —OC(O)R, —N(R)C(O)R, —N(R)N(R)₂,—N(R)C(═NR)N(R)₂, —C(═NR)N(R)₂, —C═NOR, —N(R)C(O)N(R)₂, —N(R)SO₂N(R)₂,—N(R)SO₂R, —OC(O)N(R)₂, and optionally substituted C₁₋₁₂ aliphatic, C₁₋₄alkoxy-C₁₋₄ alkyl, R¹ and R² cannot be the same except for hydrogen,B_(L2) is a bond connecting the two carbons attached to it or optionallynot a bond, each R^(1′) are independently and optionally selected from agroup consisting of hydrogen, halogen, OH, N₃, C(O)OH, CN, C(O)NH₂,C(S)NH₂, C(O)OR, R, X¹ and X² are selected from a group consisting of O,S, NH, NR, CH₂, CHR, C(R)₂, C═CH₂, C═CF₂, Y¹ and Y² are selected from agroup consisting of O, S, NH, CH₂, CF₂ or CCl₂, Z¹ and Z² areindependently selected from a group consisting of O, S, OH, SH, H, CH₃,F, BH₃ ⁻, alternatively, Z¹ and Z² are independently selected from agroup consisting of OL², OCH₂CH₂L², OCH₂OC(O)L², OCH₂OC(O)NHL²,OCH₂OC(O)N(L²)₂, OCH₂OC(O)OL², OCH₂OC(O)SL², OCH₂NHC(O)L², OCH₂SC(O)L²,OCH₂(CH₂)₁₋₆OC(O)L², OCH₂(CH₂)₁₋₆SC(O)L², OCH₂(CH₂)₁₋₆NHC(O)L²,OCH₂(CH₂)₁₋₆OC(O)OL², OCH₂(CH₂)₁₋₆SC(O)OL², OCH₂(CH₂)₁₋₆NHC(O)OL²,OCH₂O(CO)C(CH₃)₃, OCH₂O(CO)C(CH₃)₂CH₂OL², OCH₂S(CO)C(CH₃)₂CH₂OL²,OCH₂CH₂O(CO)C(CH₃)₃, OCH₂CH₂S(CO)C(CH₃)₃, OCH₂ CH₂ O(CO)C(CH₃)₂CH₂OL²,OCH₂ CH₂ S(CO)C(CH₃)₂CH₂OL², OCH₂CH₂S—SCH₂(CH₂)₀₋₆L²,OCH₂CH₂S—SCH₂(CH₂)₀₋₆OL², —O(CH₂CH₂O)₂₋₂₀L², —O(CH₂CH₂O)₂₋₂₀ C(O)OL²,—O(CH₂CH₂O)₂₋₂₀ C(O)NHL², —O(CH₂CH₂O)₂₋₂₀ CH₂CH₂NHC(O)L²,—O(CH₂CH₂O)₂₋₂₀ C(O)N(L²)₂, —S(CH₂CH₂O)₂₋₂₀L², —S(CH₂CH₂O)₂₋₂₀ C(O)OL²,—S(CH₂CH₂O)₂₋₂₀ C(O)NHL², —S(CH₂CH₂O)₂₋₂₀ C(O)N(L²)₂, where L² isindependently and optionally selected from a group consisting of H, N₃,C₁₋₂₀ straight chain alkyl, a C₁₋₂₀ straight chain alkenyl, C₁₋₂₀alkynyl, C₃₋₆ cycloalkyl, C₁₋₆ haloalkyl, a tert-butyl, a substitutedtert-butyl, a tyrosine.
 12. The compound according to claim 10, whereinthe compound of formula I′ is a compound of formula I′(a),

wherein, B¹ and B² are independently selected from a group consisting of

wherein, each R³, R⁴, R⁵, R⁸, R⁹, R¹⁰, R¹¹ and R¹² is independently andoptionally selected from a group consisting of hydrogen, halogen, —NO₂,—CN, R, —OR, —SR, —NHR, —N(R)₂, —C(O)R, —CO₂R, —C(O)C(O)R,—C(O)CH₂C(O)R, —S(O)R, —S(O)₂R, —C(O)N(R)₂, —SO₂N(R)₂, —OC(O)R,—N(R)C(O)R, —N(R)C(═NR)N(R)₂, —C(═NR)N(R)₂, —C═NOR, —N(R)SO₂N(R)₂,—N(R)SO₂R, —OC(O)N(R)₂, C₁₋₁₂ aliphatic, phenyl, R⁶ is selected from agroup consisting of NH₂, NHR, OH, —OR, —SR, —N(R)₂, R⁷ is selected froma group consisting of halogen, NH₂, NHR, OH, OR, SH, SR, —N(R)₂ when Gis a C, and R⁷ is absent when G is N, each R is independently selectedfrom a group consisting of hydrogen, an optionally substituted groupselected from C₁₋₆ aliphatic, phenyl, A, E and G are selected from agroup consisting of N, C, CR^(a) where R^(a) is independently a halogenor H, D is selected from a group consisting of N, CH, C—CN, C—NO₂, CR,C—NH₂, C—NHR, CN(R)₂, CF, CI, C—CONH₂, C—CONHR, C—CON(R)₂, C—CSN(R)₂,C—COOR, C—C(═NH)NH₂, C—OH, C—OR, C—C₁₋₄ alkylamino, C-di(C₁₋₄alkyl)amino, C-(1,3-oxazol-2-yl), C-(1,3-thiazol-2-yl), orC-(imidazol-2-yl), D¹ is independently selected from a group consistingof N, CH, C—CN, C—NO₂, CR, C—NH₂, C—NHR, CN(R)₂, CF, CI, C—CONH₂,C—CONHR, C—CON(R)₂, C—CSN(R)₂, C—COOR, C—C(═NH)NH₂, C—OH, C—OR, C—C₁₋₄alkylamino, C-di(C₁₋₄ alkyl)amino, C-(1,3-oxazol-2-yl),C-(1,3-thiazol-2-yl), or C-(imidazol-2-yl), J is independently selectedfrom a group consisting of O, S, SO₂, NH, NR, L is independentlyselected from a group consisting of C, N; wherein when L is N, R⁴ isabsent and when L is C, R⁴ is as defined above, W is selected from agroup consisting of O, S, NH, R¹ and R² are independently and optionallyselected from a group consisting of hydrogen, halogen, OH, —NO₂, —CN,—OR, —SR, —NHR, —N(R)₂, —C(O)R, —CO₂R, —C(O)CH₂C(O)R, —S(O)R, —S(O)₂R,—C(O)N(R)₂, —SO₂N(R)₂, —OC(O)R, —N(R)C(O)R, —N(R)N(R)₂,—N(R)C(═NR)N(R)₂, —C(═NR)N(R)₂, —C═NOR, —N(R)C(O)N(R)₂, —N(R)SO₂N(R)₂,—N(R)SO₂R, —OC(O)N(R)₂, and optionally substituted C₁₋₁₂ aliphatic orC₁₋₄ alkoxy-C₁₋₄ alkyl, R¹ and R² cannot be the same except forhydrogen, B_(L2) is a bond connecting the two carbons attached to it oroptionally not a bond, X³ may independently and optionally be selectedfrom, O, NH, C═O, SO₂, C═NH, NR, Z¹ and Z² are independently selectedfrom a group consisting of O⁻, S⁻, OH, SH, H, CH₃, F, BH₃ ⁻,Alternatively, Z¹ and Z² are selected from a group consisting of OL²,OCH₂CH₂L², OCH₂OC(O)L², OCH₂OC(O)NHL², OCH₂OC(O)N(L²)₂, OCH₂OC(O)OL²,OCH₂OC(O)SL², OCH₂NHC(O)L², OCH₂SC(O)L², OCH₂(CH₂)₁₋₆OC(O)L²,OCH₂(CH₂)₁₋₆SC(O)L², OCH₂(CH₂)₁₋₆NHC(O)L², OCH₂(CH₂)₁₋₆OC(O)OL²,OCH₂(CH₂)₁₋₆SC(O)OL², OCH₂(CH₂)₁₋₆NHC(O)OL², OCH₂O(CO)C(CH₃)₃,OCH₂O(CO)C(CH₃)₂CH₂OL², OCH₂S(CO)C(CH₃)₂CH₂OL², OCH₂CH₂O(CO)C(CH₃)₃,OCH₂CH₂S(CO)C(CH₃)₃, OCH₂ CH₂ O(CO)C(CH₃)₂CH₂OL², OCH₂ CH₂S(CO)C(CH₃)₂CH₂OL², OCH₂CH₂S—SCH₂(CH₂)₀₋₆L², OCH₂CH₂S—SCH₂(CH₂)₀₋₆OL²,—O(CH₂CH₂O)₂₋₂₀L², —O(CH₂CH₂O)₂₋₂₀ C(O)OL², O(CH₂CH₂O)₂₋₂₀ C(O)NHL²,—O(CH₂CH₂O)₂₋₂₀ CH₂CH₂NHC(O)L², —O(CH₂CH₂O)₂₋₂₀ C(O)N(L²)₂,—S(CH₂CH₂O)₂₋₂₀L², —S(CH₂CH₂O)₂₋₂₀ C(O)OL², —S(CH₂CH₂O)₂₋₂₀ C(O)NHL²,—S(CH₂CH₂O)₂₋₂₀ C(O)N(L²)₂, where L² is independently and optionallyselected from any of the following: H, N₃, C₁₋₂₀ straight chain alkyl, aC₁₋₂₀ straight chain alkenyl, C₁₋₂₀ alkynyl, C₃₋₆ cycloalkyl, C₁₋₆haloalkyl, a tert-butyl, a substituted tert-butyl, a tyrosine.
 13. Apharmaceutical composition, said pharmaceutical composition comprising:a. A compound according to claim 10, b. A pharmaceutically acceptablecarrier.
 14. A method for activating immune response against a targetantigen in a subject, comprising administering concurrently to thesubject a therapeutically effective dose of a compound according toclaim 10 and an antigen that corresponds to at least a portion of thetarget antigen, wherein the compound and the antigen are in particulateform.
 15. A method for inducing STING-dependent type 1 interferonproduction in a subject, comprising: administering a compositionaccording to claim 10 to the subject in an amount sufficient to induceSTING-dependent type 1 interferon production.
 16. A method of inhibitingSING-dependent type 1 interferon production in a subject in needthereof, comprising: administering a composition according to claim 10to the subject in an amount sufficient to inhibit STING-dependent type 1interferon production.
 17. A compound of formula I″

wherein: B¹ and B² are independently and optionally selected from agroup consisting of:

each R¹ and R² are independently and optionally selected from a groupconsisting of hydrogen, halogen, —NO₂, —CN, —OR, —SR, —NHR, —N(R)₂,—C(O)R, —CO₂R, —C(O)CH₂C(O)R, —S(O)R, —S(O)₂R, —C(O)N(R)₂, —SO₂N(R)₂,—OC(O)R, —N(R)C(O)R, —N(R)N(R)₂, —N(R)C(═NR)N(R)₂, —C(═NR)N(R)₂, —C═NOR,—N(R)C(O)N(R)₂, —N(R)SO₂N(R)₂, —N(R)SO₂R, —OC(O)N(R)₂, optionallysubstituted C₁₋₁₂ aliphatic, C₁₋₄ alkoxy-C₁₋₄ alkyl, R¹ and R² cannot bethe same except for hydrogen, B_(L2) is a bond connecting the twocarbons attached to it or optionally not a bond, Each R^(1′) areindependently and optionally selected from a group consisting ofhydrogen, halogen, N₃, C(O)OH, CN, C(O)NH₂, C(S)NH₂, C(O)OR, R, Each R³,R⁴, R⁵, R⁸, R⁹, R¹⁰, R¹¹ and R¹² is independently and optionallyselected from a group consisting of hydrogen, halogen, —NO₂, —CN, R,—OR, —SR, —NHR, —N(R)₂, —C(O)R, —CO₂R, —C(O)C(O)R, —C(O)CH₂C(O)R,—S(O)R, —S(O)₂R, —C(O)N(R)₂, —SO₂N(R)₂, —OC(O)R, —N(R)C(O)R,—N(R)C(═NR)N(R)₂, —C(═NR)N(R)₂, —C═NOR, —N(R)SO₂N(R)₂, —N(R)SO₂R,—OC(O)N(R)₂, C₁₋₁₂ aliphatic, phenyl, R⁶ is selected from a groupconsisting of NH₂, NHR, OH, —OR, —SR, —N(R)₂, R⁷ is selected from agroup consisting of halogen, NH₂, NHR, OH, OR, SH, SR, —N(R)₂ when G isa C, and R⁷ is absent when G is N, each R is independently selected froma group consisting of hydrogen, an optionally substituted group selectedfrom C₁₋₆ aliphatic, phenyl, A, E and G are independently selected froma group consisting of N, C, CR^(a) where R^(a) is independently halogenor H, D is selected from a group consisting of N, CH, C—CN, C—NO₂, CR,C—NH₂, C—NHR, CN(R)₂, CF, CI, C—CONH₂, C—CONHR, C—CON(R)₂, C—CSN(R)₂,C—COOR, C—C(═NH)NH₂, C—OH, C—OR, C—C₁₋₄ alkylamino, C-di(C₁₋₄alkyl)amino, C-(1,3-oxazol-2-yl), C-(1,3-thiazol-2-yl),C-(imidazol-2-yl); wherein alkyl is optionally substituted with one tothree groups selected from a group consisting of halogen, amino,hydroxyl, carboxyl, C₁₋₃ alkoxy, D¹ is selected from a group consistingof N, CH, C—CN, C—NO₂, CR, C—NH₂, C—NHR, CN(R)₂, CF, CI, C—CONH₂,C—CONHR, C—CON(R)₂, C—CSN(R)₂, C—COOR, C—C(═NH)NH₂, C—OH, C—OR, C—C₁₋₄alkylamino, C-di(C₁₋₄ alkyl)amino, C-(1,3-oxazol-2-yl),C-(1,3-thiazol-2-yl), or C-(imidazol-2-yl); wherein alkyl is optionallysubstituted with one to three groups selected from a group consisting ofhalogen, amino, hydroxyl, carboxyl, C₁₋₃ alkoxy, J is selected from agroup consisting of O, S, SO₂, NH or NR, in structure II, L is selectedfrom a group consisting of C, N; wherein when L is N, R⁴ is absent andwhen L is C, R⁴ is as defined above, W is selected from a groupconsisting of O, S or NH, X¹ and X² are selected from a group consistingof O, S, NH, NR, CH₂, CHR, C(R)₂, C═CH₂, or C═CF₂, X³ is selected from agroup consisting of O, NH, C═O, SO₂, C═NH, NR Y¹ and Y² are selectedfrom a group consisting of O, S, NH, CH₂, CF₂, CCl₂, Z¹ and Z² areselected from a group consisting of O⁻, S⁻, OH, SH, H, CH₃, F, BH₃ ⁻,Alternatively, Z¹ and Z² are selected from a group consisting of OL²,OCH₂CH₂L², OCH₂OC(O)L², OCH₂OC(O)NHL², OCH₂OC(O)N(L²)₂, OCH₂OC(O)OL²,OCH₂OC(O)SL², OCH₂NHC(O)L², OCH₂SC(O)L², OCH₂(CH₂)₁₋₆OC(O)L²,OCH₂(CH₂)₁₋₆SC(O)L², OCH₂(CH₂)₁₋₆NHC(O)L², OCH₂(CH₂)₁₋₆OC(O)OL²,OCH₂(CH₂)₁₋₆SC(O)OL², OCH₂(CH₂)₁₋₆NHC(O)OL², OCH₂O(CO)C(CH₃)₃,OCH₂O(CO)C(CH₃)₂CH₂OL², OCH₂S(CO)C(CH₃)₂CH₂OL², OCH₂CH₂O(CO)C(CH₃)₃,OCH₂CH₂S(CO)C(CH₃)₃, OCH₂ CH₂ O(CO)C(CH₃)₂CH₂OL², OCH₂ CH₂S(CO)C(CH₃)₂CH₂OL², OCH₂CH₂S—SCH₂(CH₂)₀₋₆L², OCH₂CH₂S—SCH₂(CH₂)₀₋₆OL²,—O(CH₂CH₂O)₂₋₂₀L², —O(CH₂CH₂O)₂₋₂₀ C(O)OL², O(CH₂CH₂O)₂₋₂₀ C(O)NHL²,—O(CH₂CH₂O)₂₋₂₀ CH₂CH₂NHC(O)L², —O(CH₂CH₂O)₂₋₂₀ C(O)N(L²)₂,—S(CH₂CH₂O)₂₋₂₀L², —S(CH₂CH₂O)₂₋₂₀ C(O)OL², —S(CH₂CH₂O)₂₋₂₀ C(O)NHL²,S(CH₂CH₂O)₂₋₂₀ C(O)N(L²)₂, where L² is selected from a group consistingof H, N₃, C₁₋₂₀ straight chain alkyl, a C₁₋₂₀ straight chain alkenyl,C₁₋₂₀ alkynyl, C₃₋₆ cycloalkyl, C₁₋₆ haloalkyl, a tert-butyl, asubstituted tert-butyl, a tyrosine.
 18. The compound according to claim17, wherein, B¹ and B² are independently selected from a groupconsisting of,

wherein, each R³, R⁴ and R⁵ is independently and optionally selectedfrom a group consisting of hydrogen, halogen, —NO₂, —CN, R, —OR, —SR,—NHR, —N(R)₂, —C(O)R, —CO₂R, —C(O)C(O)R, —C(O)CH₂C(O)R, —S(O)R, —S(O)₂R,—C(O)N(R)₂, —SO₂N(R)₂, —OC(O)R, —N(R)C(O)R, —N(R)C(═NR)N(R)₂,—C(═NR)N(R)₂, —C═NOR, —N(R)SO₂N(R)₂, —N(R)SO₂R, —OC(O)N(R)₂, C₁₋₁₂aliphatic, phenyl, each R is independently selected from the groupconsisting of hydrogen, C₁₋₆ aliphatic, phenyl, R¹ and R² areindependently and optionally selected from a group consisting ofhydrogen, halogen, OH, —NO₂, —CN, —OR, —SR, —NHR, —N(R)₂, —C(O)R, —CO₂R,—C(O)CH₂C(O)R, —S(O)R, —S(O)₂R, —C(O)N(R)₂, —SO₂N(R)₂, —OC(O)R,—N(R)C(O)R, —N(R)N(R)₂, —N(R)C(═NR)N(R)₂, —C(═NR)N(R)₂, —C═NOR,—N(R)C(O)N(R)₂, —N(R)SO₂N(R)₂, —N(R)SO₂R, —OC(O)N(R)₂, optionallysubstituted C₁₋₁₂aliphatic or C₁₋₄ alkoxy-C₁₋₄ alkyl, R¹ and R² cannotbe the same except for hydrogen, B_(L2) is a bond connecting the twocarbons attached to it or optionally not a bond, each R^(1′) is selectedfrom a group consisting of hydrogen, halogen, OH, N₃, C(O)OH, CN,C(O)NH₂, C(S)NH₂, C(O)OR or R, X¹ and X² are selected from a groupconsisting of O, S, NH, NR, CH₂, CHR, C(R)₂, C═CH₂, or C═CF₂, Y¹ and Y²are selected from a group consisting of O, S, NH, CH₂, CF₂ or CCl₂, Z¹and Z² are selected from a group consisting of O, S, OH, SH, H, CH₃, F,BH₃ ⁻, alternatively, Z¹ and Z² are selected from a group consisting ofOL², OCH₂CH₂L², OCH₂OC(O)L², OCH₂OC(O)NHL², OCH₂OC(O)N(L²)₂,OCH₂OC(O)OL², OCH₂OC(O)SL², OCH₂NHC(O)L², OCH₂SC(O)L²,OCH₂(CH₂)₁₋₆OC(O)L², OCH₂(CH₂)₁₋₆SC(O)L², OCH₂(CH₂)₁₋₆NHC(O)L²,OCH₂(CH₂)₁₋₆OC(O)OL², OCH₂(CH₂)₁₋₆SC(O)OL², OCH₂(CH₂)₁₋₆NHC(O)OL²,OCH₂O(CO)C(CH₃)₃, OCH₂O(CO)C(CH₃)₂CH₂OL², OCH₂S(CO)C(CH₃)₂CH₂OL²,OCH₂CH₂O(CO)C(CH₃)₃, OCH₂CH₂S(CO)C(CH₃)₃, OCH₂ CH₂ O(CO)C(CH₃)₂CH₂OL²,OCH₂ CH₂ S(CO)C(CH₃)₂CH₂OL², OCH₂CH₂S—SCH₂(CH₂)₀₋₆L²,OCH₂CH₂S—SCH₂(CH₂)₀₋₆OL², —O(CH₂CH₂O)₂₋₂₀L², —O(CH₂CH₂O)₂₋₂₀ C(O)OL²,—O(CH₂CH₂O)₂₋₂₀ C(O)NHL², —O(CH₂CH₂O)₂₋₂₀ CH₂CH₂NHC(O)L²,—O(CH₂CH₂O)₂₋₂₀ C(O)N(L²)₂, —S(CH₂CH₂O)₂₋₂₀L², —S(CH₂CH₂O)₂₋₂₀ C(O)OL²,—S(CH₂CH₂O)₂₋₂₀ C(O)NHL², —S(CH₂CH₂O)₂₋₂₀ C(O)N(L²)₂, where L² isselected from a group consisting of H, N₃, C₁₋₂₀ straight chain alkyl, aC₁₋₂₀ straight chain alkenyl, C₁₋₂₀ alkynyl, C₃₋₆ cycloalkyl, C₁₋₆haloalkyl, a tert-butyl, a substituted tert-butyl, a tyrosine.
 19. Thecompound according to claim 17, wherein the compound of formula I″ is acompound of formula I″(a),

wherein, B¹ and B² are independently selected from a group consisting of

wherein, each R³, R⁴, R⁵, R⁸, R⁹, R¹⁰, R¹¹ and R¹² is independently andoptionally selected from a group consisting of hydrogen, halogen, —NO₂,—CN, R, —OR, —SR, —NHR, —N(R)₂, —C(O)R, —CO₂R, —C(O)C(O)R,—C(O)CH₂C(O)R, —S(O)R, —S(O)₂R, —C(O)N(R)₂, —SO₂N(R)₂, —OC(O)R,—N(R)C(O)R, —N(R)C(═NR)N(R)₂, —C(═NR)N(R)₂, —C═NOR, —N(R)SO₂N(R)₂,—N(R)SO₂R, —OC(O)N(R)₂, R⁶ is selected from a group consisting of NH₂,NHR, OH, —OR, —SR, —N(R)₂, R⁷ is selected from a group consisting ofhalogen, NH₂, NHR, OH, OR, SH, SR, —N(R)₂ when G is a C, and R⁷ isabsent when G is N, each R is independently selected from the groupconsisting of hydrogen, C₁₋₆ aliphatic, phenyl, A, E and G are selectedfrom a group consisting of N, C, CR^(a) where R^(a) is independently ahalogen or H, D is selected from a group consisting of N, CH, C—CN,C—NO₂, CR, C—NH₂, C—NHR, CN(R)₂, CF, CI, C—CONH₂, C—CONHR, C—CON(R)₂,C—CSN(R)₂, C—COOR, C—C(═NH)NH₂, C—OH, C—OR, C—C₁₋₄ alkylamino, C-di(C₁₋₄alkyl)amino, C-(1,3-oxazol-2-yl), C-(1,3-thiazol-2-yl), orC-(imidazol-2-yl), D¹ is selected from a group consisting of N, CH,C—CN, C—NO₂, CR, C—NH₂, C—NHR, CN(R)₂, CF, CI, C—CONH₂, C—CONHR,C—CON(R)₂, C—CSN(R)₂, C—COOR, C—C(═NH)NH₂, C—OH, C—OR, C—C₁₋₄alkylamino, C-di(C₁₋₄ alkyl)amino, C-(1,3-oxazol-2-yl),C-(1,3-thiazol-2-yl), C-(imidazol-2-yl), J is selected from a groupconsisting of O, S, SO₂, NH, NR, L is selected from a group consistingof C or N; wherein when L is N, R⁴ is absent and when L is C, R⁴ is asdefined above, W is selected from a group consisting of O, S, NH, R¹ andR² are selected from a group consisting of hydrogen, halogen, OH, —NO₂,—CN, —OR, —SR, —NHR, —N(R)₂, —C(O)R, —CO₂R, —C(O)CH₂C(O)R, —S(O)R,—S(O)₂R, —C(O)N(R)₂, —SO₂N(R)₂, —OC(O)R, —N(R)C(O)R, —N(R)N(R)₂,—N(R)C(═NR)N(R)₂, —C(═NR)N(R)₂, —C═NOR, —N(R)C(O)N(R)₂, —N(R)SO₂N(R)₂,—N(R)SO₂R, —OC(O)N(R)₂, and optionally substituted C₁₋₁₂ aliphatic, C₁₋₄alkoxy-C₁₋₄ alkyl; R¹ and R² cannot be the same except for hydrogen,B_(L2) is a bond connecting the two carbons attached to it or optionallynot a bond, X³ is selected from a group consisting of O, NH, C═O, SO₂,C═NH, NR, Z¹ and Z² are selected from a group consisting of O⁻, S⁻, OH,SH, H, CH₃, F, BH₃ ⁻, Alternatively, Z¹ and Z² are selected from a groupconsisting of OL², OCH₂CH₂L², OCH₂OC(O)L², OCH₂OC(O)NHL²,OCH₂OC(O)N(L²)₂, OCH₂OC(O)OL², OCH₂OC(O)SL², OCH₂NHC(O)L², OCH₂SC(O)L²,OCH₂(CH₂)₁₋₆OC(O)L², OCH₂(CH₂)₁₋₆SC(O)L², OCH₂(CH₂)₁₋₆NHC(O)L²,OCH₂(CH₂)₁₋₆OC(O)OL², OCH₂(CH₂)₁₋₆SC(O)OL², OCH₂(CH₂)₁₋₆NHC(O)OL²,OCH₂O(CO)C(CH₃)₃, OCH₂O(CO)C(CH₃)₂CH₂OL², OCH₂S(CO)C(CH₃)₂CH₂OL²,OCH₂CH₂O(CO)C(CH₃)₃, OCH₂CH₂S(CO)C(CH₃)₃, OCH₂ CH₂ O(CO)C(CH₃)₂CH₂OL²,OCH₂ CH₂ S(CO)C(CH₃)₂CH₂OL², OCH₂CH₂S—SCH₂(CH₂)₀₋₆L²,OCH₂CH₂S—SCH₂(CH₂)₀₋₆OL², —O(CH₂CH₂O)₂₋₂₀L², —O(CH₂CH₂O)₂₋₂₀ C(O)OL²,O(CH₂CH₂O)₂₋₂₀ C(O)NHL², —O(CH₂CH₂O)₂₋₂₀ CH₂CH₂NHC(O)L², —O(CH₂CH₂O)₂₋₂₀C(O)N(L²)₂, —S(CH₂CH₂O)₂₋₂₀L², —S(CH₂CH₂O)₂₋₂₀ C(O)OL², —S(CH₂CH₂O)₂₋₂₀C(O)NHL², —S(CH₂CH₂O)₂₋₂₀ C(O)N(L²)₂, where L² is selected from a groupconsisting of H, N₃, C₁₋₂₀ straight chain alkyl, a C₁₋₂₀ straight chainalkenyl, C₁₋₂₀ alkynyl, C₃₋₆ cycloalkyl, C₁₋₆ haloalkyl, a tert-butyl, asubstituted tert-butyl, a tyrosine.
 20. A pharmaceutical composition,said pharmaceutical composition comprising: a. A compound according toclaim 17, b. A pharmaceutically acceptable carrier.
 21. A method foractivating immune response against a target antigen in a subject,comprising administering concurrently to the subject a therapeuticallyeffective dose of a compound according to claim 10 and an antigen thatcorresponds to at least a portion of the target antigen, wherein thecompound and the antigen are in particulate form.
 22. A method forinducing STING-dependent type 1 interferon production in a subject,comprising: administering a composition according claim 17 to thesubject in an amount sufficient to induce STING-dependent type 1interferon production.
 23. A method of inhibiting STING-dependent type 1interferon production in a subject in need thereof, comprising:administering a composition according to claim 17 to the subject in anamount sufficient to inhibit STING-dependent type 1 interferonproduction.